Substituted acrylamide derivative and pharmaceutical composition comprising the same

ABSTRACT

A pharmaceutical composition comprising a compound having Formula (I) or a pharmacologically acceptable salt thereof as an active ingredient: 
                         
[wherein,
         R 1  is, for example, a C 6 -C 10  aryl group which may be substituted with one group or more than one group selected from substituent group α; R 2  is, for example, a C 6 -C 10  aryl group which may be substituted with one group or more than one group selected from substituent group α; and X is, for example, a hydroxyl group or a C 1 -C 6  alkoxy group].

RELATED APPLICATION DATA

This application is a national phase application filed pursuant to 35CFR §371 of International Patent Application Serial No.PCT/JP2006-309445, filed May 11, 2006, entitled SUBSTITUTED ACRYLAMIDEDERIVATIVE AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME, whichapplication claims priority to Japanese Patent Application Serial No.2005-140019, filed May 12, 2005, entitled SUBSTITUTED ACRYLAMIDEDERIVATIVE AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME, whichapplications are incorporated herein by reference in their entireties.

TECHNICAL FIELD

The present invention relates to amide derivatives or pharmacologicallyacceptable salts thereof, which are valuable as drugs having excellentanti-osteoporosis activity, anti-inflammation activity, anti-rheumatoidarthritis activity, and anti-hypercalcemia activity and the like.

BACKGROUND ART

Previously, compounds having the following Formula (a) have beendisclosed in documents below.

Patent Document 1 discloses compounds, for example, shown below, whichare demonstrated to be valuable as antiviral agents.

Patent Document 2 discloses compounds, for example, shown below, whichare demonstrated to be valuable as therapeutic agents for Alzheimer'sdisease.

Example L¹ Substitution position of double bond  1 4-fluorophenyl E  2+4-fluorophenyl Z  3 2,4-difluorophenyl E  4 2,4-difluorophenyl Z  53-chlorophenyl E  6 3-chlorophenyl Z  7 2-chlorophenyl E  82-chlorophenyl Z  9 4-methoxyphenyl E 10 4-methoxyphenyl Z

Patent Document 3 discloses compounds, for example, shown below anddescribes a method for synthesizing Rev-suppressing compounds and amethod of screening the same.

A B C 2,4-dichlorophenyl phenyl cyclohexyl 2-naphthylα,α,α-trifluoro-m-toluyl 1,2,3,4-tetrahydronaphth- 1-yl 2-naphthylα,α,α-trifluoro-m-toluyl diphenylmethyl 2,4-dichlorophenylα,α,α-trifluoro-m-toluyl diphenylmethyl 2-naphthylα,α,α-trifluoro-m-toluyl 2-(p-toluyl)ethyl 2-naphthylα,α,α-trifluoro-p-toluyl diphenylmethyl p-toluyl 2,4-difluorophenyl2-hydroxyphenethyl 2-naphthyl 3-quinolinyl (1-naphthyl)methyl 2-naphthylα,α,α-trifluoro-p-toluyl 4-phenylbuto-2-yl 2,4-dichlorophenyl4-biphenylyl diphenylmethyl

Patent Document 4 discloses compounds, for example, shown below, whichare demonstrated to be valuable as antihypertensives.

However, none of the above-mentioned Patent Documents 1 to 4 mentionsactivity for bone metabolic diseases and inflammation, and therefore thepurposes of the uses of such compounds are quite different from those ofthe present invention. Furthermore, only the structures have been knownfor the compounds shown below, and the uses thereof are not known atall.

In general, in normal bone metabolism, bone resorption by osteoclasts isbalanced with bone formation by osteoblasts to maintain homeostasis. Itis thought that bone metabolic diseases are caused when the balancebetween the bone resorption and the bone formation is deteriorated.Bones retain about 99% of the total calcium in a living body and play animportant role for maintaining a constant blood calcium concentration bybone formation and bone resorption. If the osteoclasts which are mainlyresponsible for bone resorption are abnormally formed or activated, boneresorption is accelerated to increase the blood calcium concentration,and thereby bone metabolic diseases, such as hypercalcemia, are caused.

It is known that bone metastasis of cancer causes abnormal secretion ofcytokines resulting in development of hypercalcemia. In this process,bone resorption by osteoclasts is accelerated, so that the blood calciumconcentration is increased (Non-Patent Document 1). Prognosis of cancerpatients accompanied by cancerous hypercalcemia is generally poor.

Moreover, in rheumatoid arthritis, osteoarthritis and the like, abnormalformation or activation of osteoclasts is known as one of main causes ofvarious symptoms in bones and joints (Non-Patent Document 2). Patientswith rheumatoid arthritis, osteoarthritis, and the like suffer fromsevere pain, which brings considerable disadvantages to the lives of thepatients.

Furthermore, when the balance between bone resorption and bone formationcontinuously inclines toward the bone resorption due to a decrease insecretion of female hormones after menopause or due to ageing, bonedensity is lowered and osteoporosis is developed. Also in this case,osteoclasts are also responsible for the bone resorption.

When aged patients with a high risk of osteoporosis suffer fractures, apossibility of becoming bedridden is high, which is a social problem(Non-Patent Document 3).

Conventionally, for these states of diseases, hormone replacementtherapy using estrogen or the like has been conducted or a therapeuticagent such as a bisphosphonate or a calcitonin for suppressing theactivity of osteoclasts has been administered (Non-Patent Document 4).However, none of these existing agents are satisfactory agents foressentially treating hypercalcemia or bone metabolic diseases, andthereby the development of agents having high therapeutic efficacy isdesired.

-   [Patent Document 1]-   International Publication No. WO2004/002977-   [Patent Document 2]-   International Publication No. WO00/24392-   [Patent Document 3]-   Japanese Publication of International Patent Application No.    2001-506965-   [Patent Document 4]-   British Patent No. 1,113,569-   [Non-Patent Document 1]-   Jean-Jacques Body, CANCER Supplement, vol. 88, p. 3054 (2000)-   [Non-Patent Document 2]-   E. Romas, et al., Bone, vol. 30, p. 340 (2002)-   [Non-Patent Document 3]-   Bruno Fautrel, et al., Current Opinion in Rheumatology, vol. 14, p.    121 (2002)-   [Non-Patent Document 4]-   Mohammad M. Iqbal, et al., Missouri Medicine, vol. 99, p. 19 (2002)

DISCLOSURE OF INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide drugs which areexcellent as agents for improving, prophylaxis, or treatment ofosteoporosis, inflammation, rheumatoid arthritis, hypercalcemia, and thelike.

Means for Solving the Problems

The present inventors have conducted intensive studies on drugs havingexcellent blood calcium concentration-decreasing activity and bone massdecrease-suppressing activity and have found the fact that drugscomprising a compound having Formula (I) of the present invention(hereinafter referred to as a compound of the present invention) are lowin toxicity, have excellent bone resorption-suppressing activity andblood calcium concentration-decreasing activity and bone massdecrease-suppressing activity associated therewith, and are valuable forprophylaxis or treatment of bone metabolic diseases such asosteoporosis, hypercalcemia, bone metastasis of cancer, periodontaldisease, bone Paget's disease, and osteoarthritis. Thus, the presentinvention has been completed. The present invention is described below.

The present invention includes

a pharmaceutical composition for the suppression of bone resorptioncomprising a compound having Formula (I) or a pharmacologicallyacceptable salt thereof as an active ingredient:

[wherein,

R¹ represents a C₆-C₁₀ aryl group which may be substituted with onegroup or more than one group selected from substituent group α or a 5-to 10-membered heteroaryl group which may be substituted with one groupor more than one group selected from substituent group α;

R² represents a C₆-C₁₀ aryl group which may be substituted with onegroup or more than one group selected from substituent group α, a 5- to10-membered heteroaryl group which may be substituted with one group ormore than one group selected from substituent group α, or a 3- to6-membered heterocyclyl group which may be substituted with one group ormore than one group selected from substituent group α; and

X represents a hydroxyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkoxygroup which is substituted with a hydroxyl group, or a group having aformula N(R³)R⁴ (wherein R³ represents a hydrogen atom, a C₁-C₆haloalkyl group, a C₁-C₆ hydroxyalkyl group which may be protected by ahydroxyl protecting group, a C₁-C₆ alkyl group which may be substitutedwith one group or more than one group selected from substituent group β,a C₁-C₆ alkoxy group which may be substituted with a hydroxyl group, aC₃-C₁₀ cycloalkyl group which may be substituted with one group or morethan one group selected from substituent group α, a C₆-C₁₀ aryl groupwhich may be substituted with one group or more than one group selectedfrom substituent group α, or a 5- to 10-membered heteroaryl group whichmay be substituted with one group or more than one group selected fromsubstituent group α, and R⁴ represents a hydrogen atom or a C₁-C₆ alkylgroup; or R³ and R⁴, together with the nitrogen atom bound to R³ and R⁴,form a 3- to 6-membered heterocyclyl group which may be substituted withone group or more than one group selected from substituent group β), and

substituent group α represents a group consisting of hydroxyl groups,nitro groups, cyano groups, amino groups, C₁-C₆ alkylamino groups, C₁-C₆dialkylamino groups, C₃-C₆ cycloalkylamino groups, acetamido groups,halogen atoms, C₁-C₆ alkyl groups which may be substituted with onegroup or more than one group selected from substituent group β, C₁-C₆haloalkyl groups, C₃-C₁₀ cycloalkyl groups, 3- to 6-memberedheterocyclyl groups, C₃-C₆ cycloalkenyl groups, C₆-C₁₀ aryl groups whichmay be substituted with one group or more than one group selected fromsubstituent group γ, 5- to 10-membered heteroaryl groups which may besubstituted with one group or more than one group selected fromsubstituent group γ, C₁-C₆ alkoxy groups which may be substituted withone group or more than one group selected from substituent group β,C₁-C₆ haloalkoxy groups, C₁-C₆ alkoxy C₁-C₆ alkoxy groups which may besubstituted with one group or more than one group selected fromsubstituent group β, C₁-C₆ alkenyloxy groups which may be substitutedwith one group or more than one group selected from substituent group β,C₁-C₆ alkynyloxy groups which may be substituted with one group or morethan one group selected from substituent group β, C₃-C₁₀ cycloalkyloxygroups, 3- to 6-membered heterocyclyloxy groups, C₆-C₁₀ aryloxy groupswhich may be substituted with one group or more than one group selectedfrom substituent group γ, C₁-C₆ alkyleneoxy groups, C₁-C₆ alkylenedioxygroups, C₁-C₆ alkylthio groups which may be substituted with one groupor more than one group selected from substituent group β, C₁-C₆haloalkylthio groups, C₁-C₆ alkylsulfonyl groups which may besubstituted with one group or more than one group selected fromsubstituent group β, C₁-C₆ haloalkylsulfonyl groups, C₁-C₆ alkylcarbonylgroups which may be substituted with one group or more than one groupselected from substituent group β, C₁-C₆ haloalkylcarbonyl groups, andC₆-C₁₀ arylcarbonyl groups which may be substituted with one group ormore than one group selected from substituent group γ;

substituent group β represents the group consisting of hydroxyl groups,carboxyl groups, C₁-C₆ alkoxycarbonyl groups, carbamoyl groups, cyanogroups, amino groups, acetamido groups, N—C₆-C₁₀ arylacetamido groups,C₁-C₆ alkoxycarbonylamido groups, urea groups, C₃-C₁₀ cycloalkyl groupswhich may be substituted with one group or more than one group selectedfrom substituent group γ, C₃-C₆ cycloalkenyl groups, 3- to 6-memberedheterocyclyl groups, C₆-C₁₀ aryl groups which may be substituted withone group or more than one group selected from substituent group γ, 5-to 10-membered heteroaryl groups which may be substituted with one groupor more than one group selected from substituent group γ, C₁-C₆ alkoxygroups, C₆-C₁₀ aryloxy groups which may be substituted with one group ormore than one group selected from substituent group γ, and C₃-C₁₀cycloalkyloxy groups; and

substituent group γ represents a group consisting of hydroxyl groups,cyano groups, amino groups, C₁-C₆ alkylamino groups, C₁-C₆ dialkylaminogroups, C₂-C₆ cyclic amino groups, halogen atoms, C₁-C₆ alkyl groups,C₃-C₁₀ cycloalkyl groups, C₁-C₆ haloalkyl groups, C₁-C₆ alkoxy groups,C₃-C₁₀ cycloalkyloxy groups, C₁-C₆ alkylenedioxy groups, and phenylgroups].

Preferred compositions as the above-mentioned composition are:

(2) the composition according to the above (1), wherein R¹ is a phenylgroup which may be substituted with one group or more than one groupselected from substituent group α or a pyridyl group which may besubstituted with one group or more than one group selected fromsubstituent group α;

(3) the composition according to the above (1), wherein R¹ is a phenylgroup which may be substituted with one group or more than one groupselected from substituent group α;

(4) the composition according to the above (1), wherein R¹ is a phenylgroup substituted with any one group selected from the group consistingof C₁-C₆ alkoxy groups which may be substituted with one group or morethan one group selected from substituent group β, C₆-C₁₀ aryloxy groupswhich may be substituted with one group or more than one group selectedfrom substituent group γ, and C₁-C₆ haloalkoxy groups;

(5) the composition according to the above (1), wherein R¹ is a4-isobutyloxyphenyl group, a 4-(cyclopropylmethoxy)phenyl group, a4-(2-cyclopropylethoxy)phenyl group, a4-(1-methylcyclopropylmethoxy)phenyl group, a4-(3,3,3-trifluoropropyloxy)phenyl group, a4-(4,4,4-trifluorobutyloxy)phenyl group, a 4-(2-phenylethoxy)phenylgroup, a 4-(2-(4-methoxyphenyl)ethoxy)phenyl group, a4-(2-(3-methoxyphenyl)ethoxy)phenyl group, a4-(2-(4-chlorophenyl)ethoxy)phenyl group, a4-(2-(4-(N,N-dimethylamino)phenyl)ethoxy)phenyl group, a4-(4-chlorophenoxy)phenyl group, or a 4-(4-trifluoromethylphenoxy)phenylgroup;

(6) the composition according to any one of the above (1) to (5),wherein R² is a C₆-C₁₀ aryl group which may be substituted with onegroup or more than one group selected from substituent group α;

(7) the composition according to any one of the above (1) to (5),wherein R² is a phenyl group which may be substituted with one group ormore than one group selected from substituent group α;

(8) the composition according to any one of the above (1) to (5),wherein R² is a phenyl group substituted with any one group selectedfrom the group consisting of halogen atoms, C₁-C₆ alkyl groups, C₁-C₆haloalkyl groups, C₃-C₆ cycloalkyl groups, C₁-C₆ alkoxy groups, C₃-C₆cycloalkyloxy groups, C₁-C₆ haloalkoxy groups, C₁-C₆ alkylthio groups,and 5- to 10-membered heteroaryl groups;

(9) the composition according to any one of the above (1) to (5),wherein R² is a 4-fluorophenyl group, a 4-chlorophenyl group, a4-trifluoromethylphenyl group, a 4-isopropylphenyl group, a4-cyclopropylphenyl group, a 4-isopropyloxyphenyl group, a4-difluoromethoxyphenyl group, a 4-trifluoromethoxyphenyl group, a4-(2,2,2-trifluoroethoxy)phenyl group, a 4-(2,2-difluoroethoxy)phenylgroup, a 4-cyclopropyloxyphenyl group, a 4-ethoxyphenyl group, a4-methylthiophenyl group, or a 4-(1H-pyrrol-1-yl)phenyl group;

(10) the composition according to any one of the above (1) to (9),wherein X is a group having a formula N(R³)R⁴ (wherein R³ represents aC₁-C₆ haloalkyl group, a C₁-C₆ alkyl group which may be substituted withone group or more than one group selected from substituent group β, or aC₁-C₆ hydroxyalkyl group which may be protected by a hydroxyl protectinggroup, and R⁴ represents a hydrogen atom);

(11) the composition according to any one of the above (1) to (9),wherein X is a group having a formula N(R³)R⁴ (where R³ represents aC₂-C₃ haloalkyl group, a C₂-C₃ hydroxyalkyl group which may be protectedby a hydroxyl protecting group, or a C₁-C₃ alkyl group substituted witha 1-hydroxycyclopropyl group, and R⁴ represents a hydrogen atom);

(12) the composition according to any one of (1) to (9), wherein X is a2-fluoroethylamino group, a 2,2-difluoroethylamino group, a2-hydroxyethylamino group, a 1-(2-hydroxypropyl)amino group, a1-hydroxycyclopropylmethylamino group, a 2-acetoxyethylamino group, a2-(morpholin-4-ylacetoxy)ethylamino group, or a2-(3-carboxypropionyloxy)ethylamino group; and

(13) the composition according to any one of the above (1) to (12),wherein the chemical structure regarding the position of the acrylamidemoiety in Formula (I) is Z.

Furthermore, the present invention includes

(14) a compound having Formula (I′) or a pharmacologically acceptablesalt thereof:

[wherein,

R⁵ and R⁶ each independently represent a substituent on a benzene ring,the substituent being selected from substituent group α;

R⁷ represents a hydrogen atom, a C₁-C₆ haloalkyl group, a C₁-C₆hydroxyalkyl group which may be protected by a hydroxyl protectinggroup, a C₁-C₆ alkyl group which may be substituted with one group ormore than one group selected from substituent group β, a C₆-C₁₀ arylgroup which may be substituted with one group or more than one groupselected from substituent group α, or a C₃-C₁₀ cycloalkyl group whichmay be substituted with one group or more than one group selected fromsubstituent group α;

m represents an integer of 1 to 3;

n represents an integer of 1 to 3;

the numerals on each benzene ring represent the position number of eachsubstitution;

substituent group α represents a group consisting of hydroxyl groups,nitro groups, cyano groups, amino groups, C₁-C₆ alkylamino groups, C₁-C₆dialkylamino groups, C₃-C₆ cycloalkylamino groups, acetamido groups,halogen atoms, C₁-C₆ alkyl groups which may be substituted with onegroup or more than one group selected from substituent group β, C₁-C₆haloalkyl groups, C₃-C₁₀ cycloalkyl groups, 3- to 6-memberedheterocyclyl groups, C₃-C₆ cycloalkenyl groups, C₆-C₁₀ aryl groups whichmay be substituted with one group or more than one group selected fromsubstituent group γ, 5- to 10-membered heteroaryl groups which may besubstituted with one group or more than one group selected fromsubstituent group γ, C₁-C₆ alkoxy groups which may be substituted withone group or more than one group selected from substituent group β,C₁-C₆ haloalkoxy groups, C₁-C₆ alkoxy C₁-C₆ alkoxy groups which may besubstituted with one group or more than one group selected fromsubstituent group β, C₁-C₆ alkenyloxy groups which may be substitutedwith one group or more than one group selected from substituent group β,C₁-C₆ alkynyloxy groups which may be substituted with one group or morethan one group selected from substituent group β, C₃-C₁₀ cycloalkyloxygroups, 3- to 6-membered heterocyclyloxy groups, C₆-C₁₀ aryloxy groupswhich may be substituted with one group or more than one group selectedfrom substituent group γ, C₁-C₆ alkyleneoxy groups, C₁-C₆ alkylenedioxygroups, C₁-C₆ alkylthio groups which may be substituted with one groupor more than one group selected from substituent group β, C₁-C₆haloalkylthio groups, C₁-C₆ alkylsulfonyl groups which may besubstituted with one group or more than one group selected fromsubstituent group β, C₁-C₆ haloalkylsulfonyl groups, C₁-C₆ alkylcarbonylgroups which may be substituted with one group or more than one groupselected from substituent group β, C₁-C₆ haloalkylcarbonyl groups, andC₆-C₁₀ arylcarbonyl groups which may be substituted with one group ormore than one group selected from substituent group γ;

substituent group β represents the group consisting of hydroxyl groups,carboxyl groups, C₁-C₆ alkoxycarbonyl groups, carbamoyl groups, cyanogroups, amino groups, acetamido groups, N—C₆-C₁₀ arylacetamido groups,C₁-C₆ alkoxycarbonylamido groups, urea groups, C₃-C₁₀ cycloalkyl groupswhich may be substituted with one group or more than one group selectedfrom substituent group γ, C₃-C₆ cycloalkenyl groups, 3- to 6-memberedheterocyclyl groups, C₆-C₁₀ aryl groups which may be substituted withone group or more than one group selected from substituent group γ, 5-to 10-membered heteroaryl groups which may be substituted with one groupor more than one group selected from substituent group γ, C₁-C₆ alkoxygroups, C₆-C₁₀ aryloxy groups which may be substituted with one group ormore than one group selected from substituent group γ, and C₃-C₁₀cycloalkyloxy groups; and

substituent group γ represents the group consisting of hydroxyl groups,cyano groups, amino groups, C₁-C₆ alkylamino groups, C₁-C₆ dialkylaminogroups, C₂-C₆ cyclic amino groups, halogen atoms, C₁-C₆ alkyl groups,C₃-C₁₀ cycloalkyl groups, C₁-C₆ haloalkyl groups, C₁-C₆ alkoxy groups,C₃-C₁₀ cycloalkyloxy groups, C₁-C₆ alkylenedioxy groups, and phenylgroups], wherein the compounds having Formula (I′) are not the followingcompounds:

The above-mentioned compound or a pharmacologically acceptable saltthereof is preferably:

(15) the compound or a pharmacologically acceptable salt thereofaccording to the above (14), wherein R⁵ is any one group selected fromthe group consisting of halogen atoms, C₁-C₆ alkyl groups which may besubstituted with one group or more than one group selected fromsubstituent group β, C₁-C₆ haloalkyl groups, C₃-C₆ cycloalkyl groups,C₁-C₆ alkoxy groups which may be substituted with one group or more thanone group selected from substituent group β, C₆-C₁₀ aryloxy groups whichmay be substituted with one group or more than one group selected fromsubstituent group γ, C₁-C₆ haloalkoxy groups, and C₃-C₆ cycloalkyloxygroups;

(16) the compound or a pharmacologically acceptable salt thereofaccording to the above (14), wherein R⁵ is any one group selected fromthe group consisting of C₁-C₆ alkoxy groups which may be substitutedwith one group or more than one group selected from substituent group β,C₆-C₁₀ aryloxy groups which may be substituted with one group or morethan one group selected from substituent group γ, and C₁-C₆ haloalkoxygroups;

(17) the compound or a pharmacologically acceptable salt thereofaccording to the above (14), wherein R⁵ is an isobutyloxy group, acyclopropylmethoxy group, a 2-cyclopropylethoxy group, a1-methylcyclopropylmethoxy group, a 3,3,3-trifluoropropyloxy group, a4,4,4-trifluorobutyloxy group, a 2-phenylethoxy group, a2-(4-methoxyphenyl)ethoxy group, a 2-(3-methoxyphenyl)ethoxy group, a2-(4-chlorophenyl)ethoxy group, a 2-(4-(N,N-dimethylamino)phenyl)ethoxygroup, a 4-chlorophenoxy group, or a 4-trifluoromethylphenoxy group;

(18) the compound or a pharmacologically acceptable salt thereofaccording to any one of the above (14) to (17), wherein R⁶ is any onegroup selected from the group consisting of halogen atoms, C₁-C₆ alkylgroups, C₁-C₆ haloalkyl groups, C₃-C₆ cycloalkyl groups, C₁-C₆ alkoxygroups, C₃-C₆ cycloalkyloxy groups, C₁-C₆ haloalkoxy groups, C₁-C₆alkylthio groups, and 5- to 10-membered heteroaryl groups;

(19) the compound or a pharmacologically acceptable salt thereofaccording to any one of the above (14) to (17), wherein R⁶ is a fluorineatom, a chlorine atom, a trifluoromethyl group, an isopropyl group, acyclopropyl group, an isopropyloxy group, a difluoromethoxy group, atrifluoromethoxy group, a 2,2,2-trifluoroethoxy group, a2,2-difluoroethoxy group, a cyclopropyloxy group, an ethoxy group, amethylthio group, or a 1H-pyrrol-1-yl group;

(20) the compound or a pharmacologically acceptable salt thereofaccording to any one of the above (14) to (17), wherein R⁶ is an ethoxygroup, a trifluoromethyl group, a cyclopropyl group, a cyclopropyloxygroup, a difluoromethoxy group, a trifluoromethoxy group, or a2,2-difluoroethoxy group;

(21) the compound or a pharmacologically acceptable salt thereofaccording to any one of the above (14) to (20), wherein R⁷ is a C₁-C₆haloalkyl group, a C₁-C₆ alkyl group which may be substituted with onegroup or more than one group selected from substituent group β, or aC₁-C₆ hydroxyalkyl group which may be protected by a hydroxyl protectinggroup;

(22) the compound or a pharmacologically acceptable salt thereofaccording to any one of the above (14) to (20), wherein R⁷ is a C₂-C₃haloalkyl group, a C₂-C₃ hydroxyalkyl group which may be protected by ahydroxyl protecting group, or a C₁-C₃ alkyl group substituted with1-hydroxycyclopropyl group;

(23) the compound or a pharmacologically acceptable salt thereofaccording to any one of the above (14) to (20), wherein R⁷ is a2-fluoroethyl group, a 2,2-difluoroethyl group, a 2-hydroxyethyl group,a 2-hydroxypropyl group, a 1-hydroxycyclopropylmethyl group, a2-acetoxyethyl group, a 2-(morpholin-4-ylacetoxy)ethyl group, or a2-(3-carboxypropionyloxy)ethyl group;

(24) the compound or a pharmacologically acceptable salt thereofaccording to any one of the above (14) to (23), wherein m and n are each1;

(25) the compound or a pharmacologically acceptable salt thereofaccording to the above (24), wherein R⁵ is substituted at the 4-positionof the benzene ring of Formula (I′), and R⁶ substituted at the4′-position of the benzene ring of Formula (I′); and

(26) a compound or its pharmacologically acceptable salt, the compoundbeing selected from the followings:

-   4-(2-cyclopropylethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(2-cyclopropylethoxy)-N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(2-cyclopropylethoxy)-N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(2-cyclopropylethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   4-(2-cyclopropylethoxy)-N-(2-[4-(2,2-difluoroethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(2-cyclopropylethoxy)-N-(2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   2-{[(2Z)-2-{[4-(2-cyclopropylethoxy)benzoyl]amino}-3-(4-cyclopropylphenyl)propen-2-oyl]amino}ethyl    acetate,-   2-{[(2Z)-2-{[4-(2-cyclopropylethoxy)benzoyl]amino}-3-(4-cyclopropylphenyl)propen-2-oyl]amino}ethyl    succinate,-   4-(2-cyclopropylethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,-   4-(2-cyclopropylethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(1H-pyrrol-1-yl)phenyl]vinyl}benzamide,-   N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-cyclopropylethoxy)benzamide,-   N-[1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   N-(2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(methylthio)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   4-{2-[4-(dimethylamino)phenyl]ethoxy)-N-[1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide,-   4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   N-(2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(4,4,4-trifluorobutoxy)benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(4,4,4-trifluorobutoxy)benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-{1-{[(2,2-difluoroethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-{1-({[(2S)-2-hydroxypropyl]amino}carbonyl)-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[4-(trifluoromethyl)phenoxy]benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide,-   4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,    and-   4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide;    and

(27) the compound or a pharmacologically acceptable salt thereofaccording to any one of the above (14) to (26), wherein the chemicalstructure regarding the position of the acrylamide moiety is Z.

Furthermore, the present invention provides

(28) a pharmaceutical composition comprising one or more compounds or apharmacologically acceptable salt thereof according to any one of theabove (14) to (27) as an active ingredient;

(29) the composition according to the above (28), the composition beinga bone resorption-suppressing agent;

(30) the composition according to any one of the above (1) to (13),(28), and (29), the composition being used for decreasing blood calciumconcentration; and

(31) the composition according to any one of the above (1) to (13),(28), and (29), the composition being used for suppressing a decrease inbone mass.

Furthermore, the present invention provides

(32) the composition according to any one of the above (1) to (13),(28), and (29), the composition being used for improving bonemetabolism;

(33) the composition according to any one of the above (1) to (13),(28), and (29), the composition being used for prophylaxis or treatmentof a bone metabolic disease;

(34) the composition according to the above (33), wherein the bonemetabolic disease is osteoporosis;

(35) the composition according to the above (33), wherein the bonemetabolic disease is hypercalcemia; and

(36) the composition according to any one of the above (1) to (13),(28), and (29), the composition being used for suppressing bonemetastasis of cancer.

Furthermore, the present invention provides

(37) a method for improving bone metabolism, wherein an effective amountof a composition according to any one of the above (1) to (13), (28),and (29) is administered to a mammal;

(38) a method for the prophylaxis or treatment of a bone metabolicdisease, wherein an effective amount of a composition according to anyone of the above (1) to (13), (28), and (29) is administered to amammal;

(39) a method for the prophylaxis or treatment of osteoporosis, whereinan effective amount of a composition according to any one of the above(1) to (13), (28), and (29) is administered to a mammal;

(40) a bone resorption-suppressing agent, the agent significantlydecreasing serum calcium concentration of a mammal administered with theagent; and

(41) the bone resorption-suppressing agent according to the above (40),wherein the dose of the agent as an active ingredient is from 0.001mg/kg to 100 mg/kg.

(Definition, Preferred Groups, and So On)

For substituent group α, preferred substituents are those in the groupconsisting of halogen atoms, C₁-C₆ alkyl groups which may be substitutedwith one group or more than one group selected from substituent group β,C₁-C₆ haloalkyl groups, C₃-C₁₀ cycloalkyl groups, 5- to 10-memberedheteroaryl groups which may be substituted with one group or more thanone group selected from substituent group γ, C₁-C₆ alkoxy groups whichmay be substituted with one group or more than one group selected fromsubstituent group β, C₁-C₆ haloalkoxy groups, C₃-C₁₀ cycloalkyloxygroups, and C₁-C₆ alkylthio groups which may be substituted with onegroup or more than one group selected from substituent group β.

For substituent group β, preferred substituents are those in the groupconsisting of C₃-C₁₀ cycloalkyl groups which may be substituted with onegroup or more than one group selected from substituent group γ, C₆-C₁₀aryl groups which may be substituted with one group or more than onegroup selected from substituent group γ, 5- to 10-membered heteroarylgroups which may be substituted with one group or more than one groupselected from substituent group γ, and C₆-C₁₀ aryloxy groups which maybe substituted with one group or more than one group selected fromsubstituent group γ.

For substituent group γ, preferred substituents are those in the groupconsisting of hydroxyl groups, cyano groups, C₁-C₆ dialkylamino groups,halogen atoms, C₁-C₆ alkyl groups, C₁-C₆ haloalkyl groups, C₃-C₁₀cycloalkyl groups, C₁-C₆ alkoxy groups, C₁-C₆ alkylenedioxy groups, andC₃-C₁₁ cycloalkyloxy groups.

Among the compounds having Formula (I), compounds having Formula (I′)are preferred. Of the compounds having Formula (I′), the compounds inwhich each m and n is 1 are preferred. The compounds in which R⁵ is asubstituent at the 4-position and R⁶ is a substituent at the 4′-positionare further preferred.

The C₆-C₁₀ aryl groups of the “C₆-C₁₀ aryl group which may besubstituted with one group or more than one group selected fromsubstituent group α” in the above definitions of R¹, R², R³, and R⁷ andof the “C₆-C₁₀ aryl group which may be substituted with one group ormore than one group selected from substituent group γ” in thedefinitions of substituent groups α and β may be condensed with othercyclic groups. Examples of such C₆-C₁₀ aryl groups include phenylgroups, indenyl groups, indanyl groups, naphthyl groups, and chromanylgroups, and phenyl groups are preferred.

The term “may be substituted” in the above “C₆-C₁₀ aryl group which maybe substituted with one group or more than one group selected fromsubstituent group α” preferably means substitution with one or twogroups, and the term “may be substituted” in the “C₆-C₁₀ aryl groupwhich may be substituted with one group or more than one group selectedfrom substituent group γ” preferably means non-substitution orsubstitution with one group.

The 5- to 10-membered heteroaryl group of the “5- to 10-memberedheteroaryl group which may be substituted with one group or more thanone group selected from substituent group α” in the definitions of R¹,R², and R³ and the 5- to 10-membered heteroaryl group of the “5- to10-membered heteroaryl group which may be substituted with one group ormore than one group selected from substituent group γ” in thedefinitions of substituent groups α and β are cyclic groups having 3 to6 carbon atoms and which contain a nitrogen atom, an oxygen atom, and/ora sulfur atom. Examples of such 5- to 10-membered heteroaryl groupsinclude furyl groups, thienyl groups, pyrrolyl groups, pyrazolyl groups,imidazolyl groups, oxazolyl groups, isoxazolyl groups, thiazolyl groups,isothiazolyl groups, triazolyl groups, tetrazolyl groups, pyranylgroups, pyridyl groups, pyridazinyl groups, pyrimidinyl groups, andpyrazinyl groups. Among them, 5- or 6-membered heteroaryl groups arepreferred. The above “5- to 10-membered heteroaryl group” may becondensed with another cyclic group such as an indolyl group, abenzofuranyl group, a benzothienyl group, a quinolyl group, anisoquinolyl group, a quinazolinyl group, a tetrahydroquinolyl group, ora tetrahydroisoquinolyl group. R¹ is preferably a pyridyl group, R² ispreferably a pyridyl group, a triazolyl group, or a pyrrolyl group, andR³ is preferably a pyridyl group. Among substituent group β, abenzothiazoyl group, a pyridyl group, and a pyrrolyl group arepreferred.

The term “may be substituted” in the above “5- to 10-membered heteroarylgroup which may be substituted with one group or more than one groupselected from substituent group α” preferably means substitution withone or two groups, and the term “may be substituted” in the “5- to10-membered heteroaryl group which may be substituted with one group ormore than one group selected from substituent group γ” preferably meansnon-substitution or substitution with one group.

The “3- to 6-membered heterocyclyl groups” of the “3- to 6-memberedheterocyclyl group which may be substituted with one group or more thanone group selected from substituent group α” in the definition of R²,the “3- to 6-membered heterocyclyl group which may be substituted withone group or more than one group selected from substituent group β” inthe definitions of R³ and R⁷, and the “3- to 6-membered heterocyclylgroup” in the definitions of substituent groups α and β can be, forexample, an azetidinyl group, a pyrrolidinyl group, a pyrrolinyl group,an imidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, apyrazolinyl group, an oxazolidinyl group, a thiazolidinyl group, apiperidyl group, a tetrahydropyridyl group, a dihydropyridyl group, apiperazinyl group, a morpholinyl group, a thiomorpholinyl group, ahomopiperidyl group, a tetrahydrofuryl group, a tetrahydropyranyl group,a 2,5-dioxopyrrolidinyl group, and a 2,6-dioxopiperazinyl group. Insubstituent group β, a pyrrolidinyl group, a piperidyl group, amorpholinyl group, and a tetrahydrofuryl group are preferred.

The “3- to 6-membered heterocyclyl groups” of the “3- to 6-memberedheterocyclyl group” in the definitions of substituent groups α and β maybe condensed with other cyclic groups such as a1,3-dioxo-2,3-dihydro-1H-isoindolyl group or a2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl group.

The C₁-C₆ alkoxy groups of the “C₁-C₆ alkoxy group” in the definitionsof X and substituent groups β and γ and of the “C₁-C₆ alkoxy group whichmay be substituted with a hydroxyl group” or the “C₁-C₆ alkoxy groupsubstituted with a hydroxyl group” in the definitions of R³ and X andthe C₁-C₆ alkoxy group of the “C₁-C₆ alkoxy group which may besubstituted with one group or more than one group selected fromsubstituent group β” in the definition of substituent group α can be,for example, linear or branched alkoxy groups having 1 to 6 carbonatoms; and are preferably a methoxy group, an ethoxy group, a propoxygroup, an isopropoxy group, a butoxy group, or an isobutoxy group.

The term “substituted” in the above “C₁-C₆ alkoxy group substituted witha hydroxyl group” means substitution with one to three groups and,preferably, substitution with one or two groups.

The C₁-C₆ alkyl groups of the above “C₁-C₆ alkyl group” in thedefinitions of R³, R⁴, and substituent group γ and of the “C₁-C₆ alkylgroup which may be substituted with one group or more than one groupselected from substituent group β” in the definitions of R³, R⁷, andsubstituent group α can be, for example, linear or branched alkyl groupshaving 1 to 6 carbon atoms; and are preferably a methyl group, an ethylgroup, a propyl group, an isopropyl group, or a butyl group.

The term “may be substituted” of the above “C₁-C₆ alkyl group which maybe substituted with one group or more than one group selected fromsubstituent group β” preferably means substitution with one or twogroups.

Examples of the “hydroxy protecting group” in the definitions of R³ andR⁷ include “aliphatic acyl groups”, for example, alkylcarbonyl groupssuch as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl,pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl,3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl,3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl,tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl,14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl,15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl,nonadecanoyl, icosanoyl, and henicosanoyl; aminated alkylcarbonylgroups, which are the above-mentioned alkylcarbonyl groups substitutedwith substituted an amino group, such as morpholin-4-ylacetyl,piperidin-1-ylacetyl, and pyrrolidin-1-ylacetyl; carboxylatedalkylcarbonyl groups, such as succinoyl, glutaroyl, and azipoyl;halogeno C₁-C₆ alkylcarbonyl groups, such as chloroacetyl,dichloroacetyl, trichloroacetyl, and trifluoroacetyl; C₁-C₆ alkoxy C₁-C₆alkylcarbonyl groups, such as methoxyacetyl; unsaturated alkylcarbonylgroups, such as (E)-2-methyl-2-butenoyl; “aromatic acyl groups”, forexample, arylcarbonyl groups, such as benzoyl, α-naphthoyl, andβ-naphthoyl; halogeno-arylcarbonyl groups, such as 2-bromobenzoyl and4-chlorobenzoyl; lower-alkylated arylcarbonyl groups, such as2,4,6-trimethylbenzoyl and 4-toluoyl; lower-alkoxylated arylcarbonylgroups, such as 4-anisoyl; carboxylated arylcarbonyl groups, such as2-carboxybenzoyl, 3-carboxybenzoyl, and 4-carboxybenzoyl; nitratedarylcarbonyl groups, such as 4-nitrobenzoyl and 2-nitrobenzoyl; loweralkoxycarbonylated arylcarbonyl groups, such as2-(methoxycarbonyl)benzoyl; and arylated arylcarbonyl groups, such as4-phenylbenzoyl; “tetrahydropyranyl or tetrahydrothiopyranyl groups”,such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl,4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, and4-methoxytetrahydrothiopyran-4-yl; “tetrahydrofuranyl ortetrahydrothiofuranyl groups, such as tetrahydrofuran-2-yl andtetrahydrothiofuran-2-yl; “silyl groups”, for example, tri(loweralkyl)silyl groups, such as trimethylsilyl, triethylsilyl,isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl,methyldi-t-butylsilyl, and triisopropylsilyl; and tri(lower alkyl)silylgroups substituted with 1 or 2 aryl groups, such as diphenylmethylsilyl,diphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl;“alkoxymethyl groups”, for example, lower alkoxymethyl groups, such asmethoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl,propoxymethyl, isopropoxymethyl, butoxymethyl, and t-butoxymethyl; loweralkoxylated lower alkoxymethyl groups, such as 2-methoxyethoxymethyl;and halogeno-lower alkoxy methyl groups, such as2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl; “substitutedethyl groups”, for example, lower alkoxylated ethyl groups, such as1-ethoxyethyl and 1-(isopropoxy)ethyl; and halogenated ethyl groups,such as 2,2,2-trichloroethyl; “aralkyl groups”, for example, lower alkylgroups substituted with 1 to 3 aryl groups, such as benzyl,α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl,α-naphthyldiphenylmethyl, and 9-anthrylmethyl; and lower alkyl groupssubstituted with 1 to 3 aryl groups the aryl ring of which issubstituted with a lower alkyl, lower alkoxy, halogen, or cyano groupsuch as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl,4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl,4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, methyl, andpiperonyl; “alkoxycarbonyl groups”, for example, lower alkoxycarbonylgroups, such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, andisobutoxycarbonyl; and lower alkoxycarbonyl groups substituted with ahalogen or tri(lower alkyl)silyl group, such as2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl;“alkenyloxycarbonyl groups”, such as vinyloxycarbonyl andallyloxycarbonyl; “arylaminocarbonyl groups”, such asphenylaminocarbonyl groups; and “aralkyloxycarbonyl groups in which thearyl ring may be substituted with 1 or 2 lower alkoxy or a nitro group”,such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, and4-nitrobenzyloxycarbonyl. The “protecting group for a hydroxy group” ispreferably an aliphatic acyl group, more preferably an alkylcarbonylgroup, an aminated alkylcarbonyl group, or a carboxylated alkylcarbonylgroup, and further preferably an acetyl, morpholin-4-ylacetyl, orsuccinoyl group.

The C₁-C₆ hydroxyalkyl group of the “C₁-C₆ hydroxyalkyl group which maybe protected by a hydroxyl protecting group” in the definitions of R³and R⁷ can be, for example, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, or 6-hydroxyhexyl; andis preferably a hydroxymethyl, 2-hydroxyethyl, or 3-hydroxypropyl group.

The C₃-C₁₀ cycloalkyl group of the “C₃-C₁₀ cycloalkyl group which may besubstituted with one group or more than one group selected fromsubstituent group α” in the definitions of R³ and R⁷ and the C₃-C₁₀cycloalkyl groups of the “C₃-C₁₀ cycloalkyl group” in the definition ofsubstituent group α and of the “C₃-C₁₀ cycloalkyl group which may besubstituted with one group or more than one group selected fromsubstituent group γ” in the definition of substituent group β are, forexample, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, acyclohexyl group, a cycloheptyl group, or an adamantyl group.

The term “may be substituted” in the above “C₃-C₁₀ cycloalkyl groupwhich may be substituted with one group or more than one group selectedfrom substituent group α” and in the “C₃-C₁₀ cycloalkyl group which maybe substituted with one group or more than one group selected fromsubstituent group γ” means unsubstituted or mono- to tri-substituted.

The “C₁-C₆ alkylamino group” in the definitions of substituent groups αand γ is an amino group substituted with one of the above-mentionedC₁-C₆ alkyl groups, such as an amino group substituted with a linear orbranched alkyl group having 1 to 6 carbon atoms; and is preferably amethylamino group, an ethylamino group, a propylamino group, anisopropylamino group, or a butylamino group; and more preferably amethylamino group, an ethylamino group, or a propylamino group.

The “C₁-C₆ dialkylamino group” in the definitions of substituent groupsα and γ is an amino group substituted with two of the above-mentionedC₁-C₆ alkyl groups and can be, for example, an amino group substitutedwith two linear or branched alkyl groups each having 1 to 6 carbonatoms; and is preferably a dimethylamino group, a diethylamino group, adipropylamino group, a diisopropylamino group, or a dibutylamino group;and more preferably a dimethylamino group or a diethylamino group.

The “C₃-C₆ cycloalkylamino group” in the definition of substituent groupα can be, for example, a cyclopropylamino group, a cyclobutylaminogroup, a cyclopentylamino group, or a cyclohexylamino group; and ispreferably a cyclopentylamino group or a cyclohexylamino group.

The “C₁-C₆ haloalkyl group” in the definitions of R³, R⁵, R⁶, andsubstituent groups α and γ is the above-mentioned C₁-C₆ alkyl groupsubstituted with as many halogen atoms as possible. Examples of theC₁-C₆ haloalkyl group include a fluoromethyl group, a difluoromethylgroup, a trifluoromethyl group, a fluoroethyl group, a difluoroethylgroup, a trifluoroethyl group, a fluoropropyl group, a difluoropropylgroup, a trifluoropropyl group, a fluorobutyl group, a difluorobutylgroup, a trifluorobutyl group, a fluoropentyl group, a difluoropentylgroup, a trifluoropentyl group, a fluorohexyl group, a difluorohexylgroup, a trifluorohexyl group, a pentafluoroethyl group, ahexafluoropropyl group, a nonafluorobutyl group, a chloromethyl group, adichloromethyl group, a trichloromethyl group, a chloroethyl group, adichloroethyl group, a trichloroethyl group, a chloropropyl group, adichloropropyl group, a trichloropropyl group, a chlorobutyl group, adichlorobutyl group, a trichlorobutyl group, a chloropentyl group, adichloropentyl group, a trichloropentyl group, a chlorohexyl group, adichlorohexyl group, a trichlorohexyl groups, a pentachloroethyl group,a hexachloropropyl group, and a nonachlorobutyl group. The C₁-C₆haloalkyl group is preferably a fluoromethyl group, a difluoromethylgroup, a trifluoromethyl group, a fluoroethyl group, a difluoroethylgroup, a trifluoroethyl group, a fluoropropyl group, a difluoropropylgroup, or a trifluoropropyl group; and more preferably a fluoromethylgroup, a difluoromethyl group, a trifluoromethyl group, a fluoroethylgroup, a difluoroethyl group, or a trifluoroethyl group.

The “C₃-C₆ cycloalkenyl group” in the definitions of substituent groupsα and β can be, for example, a cyclopropenyl group, a cyclobutenylgroup, a cyclopentenyl group, or a cyclohexenyl group; and is preferablya cyclopentenyl group or a cyclohexyl group.

The “C₁-C₆ haloalkoxy group” in the definition of substituent group α isthe above-mentioned C₁-C₆ haloalkyl group the alkyl terminus of which issubstituted with an oxygen atom and can be, for example, a fluoromethoxygroup, a difluoromethoxy group, a trifluoromethoxy group, a fluoroethoxygroup, a difluoroethoxy group, a trifluoroethoxy group, a fluoropropoxygroup, a difluoropropoxy group, a trifluoropropoxy group, a fluorobutoxygroup, a difluorobutoxy group, a trifluorobutoxy group, afluoropentyloxy group, a difluoropentyloxy group, a trifluoropentyloxygroup, a fluorohexyloxy group, a difluorohexyloxy group, atrifluorohexyloxy group, a pentafluoroethoxy group, a hexafluoropropoxygroup, a nonafluorobutoxy group, a chloromethoxy group, adichloromethoxy group, a trichloromethoxy group, a chloroethoxy group, adichloroethoxy group, a trichloroethoxy group, a chloropropoxy group, adichloropropoxy group, a trichloropropoxy group, a chlorobutoxy group, adichlorobutoxy group, a trichlorobutoxy group, a chloropentyloxy group,a dichloropentyloxy group, a trichloropentyloxy group, a chlorohexyloxygroup, a dichlorohexyloxy group, a trichlorohexyloxy group, apentachloroethoxy group, a hexachloropropoxy group, or anonachlorobutoxy group; and is preferably a fluoromethoxy group, adifluoromethoxy group, a trifluoromethoxy group, a fluoroethoxy group, adifluoroethoxy group, a trifluoroethoxy group, a fluoropropoxy group, adifluoropropoxy group, or a trifluoropropoxy group; and more preferablya fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxygroup, a fluoroethoxy group, a difluoroethoxy group, or atrifluoroethoxy group.

The C₁-C₆ alkoxy C₁-C₆ alkoxy group of the “C₁-C₆ alkoxy C₁-C₆ alkoxygroup which may be substituted with one group or more than one groupselected from substituent group β” in the definition of substituentgroup α is the above-mentioned C₁-C₆ alkoxy group substituted with oneof the above-mentioned C₁-C₆ alkoxy groups and can be, for example, amethoxymethoxy group, a 2-methoxyethoxy group, a 3-methoxypropoxy group,a 4-methoxybutoxy group, a 5-methoxypentyloxy group, a 6-methoxyhexyloxygroup, an ethoxymethoxy group, a 2-ethoxyethoxy group, a 3-ethoxypropoxygroup, a 4-ethoxybutoxy group, a 5-ethoxypentyloxy group, or a6-ethoxyhexyloxy group; and is preferably a 2-methoxyethoxy group, a3-methoxypropoxy group, a 4-methoxybutoxy group, or a 5-methoxypentyloxygroup.

The C₁-C₆ alkenyloxy group of the “C₁-C₆ alkenyloxy group which may besubstituted with one group or more than one group selected fromsubstituent group β” in the definition of substituent group α can be,for example, a vinyloxy group, a 1-propenyloxy group, a 2-propenyloxygroup, a 1-butenyloxy group, a 2-butenyloxy group, a 3-butenyloxy group,a 1-pentenyloxy group, a 2-pentenyloxy group, a 3-pentenyloxy group, a4-pentenyloxy group, a 1-hexenyloxy group, a 2-hexenyloxy group, a3-hexenyloxy group, a 4-hexenyloxy group, or a 5-hexenyloxy group; andis preferably a 1-propenyloxy group, a 2-propenyloxy group, a1-butenyloxy group, a 2-butenyloxy group, or a 3-butenyloxy group.

The C₁-C₆ alkynyloxy group of the “C₁-C₆ alkynyloxy group which may besubstituted with one group or more than one group selected fromsubstituent group” in the definition of substituent group α can be, forexample, a 1-propynyloxy group, a 2-propynyloxy group, a 1-butynyloxygroup, a 2-butynyloxy group, a 3-butynyloxy group, a 1-pentynyloxygroup, a 2-pentynyloxy group, a 3-pentynyloxy group, a 4-pentynyloxygroup, a 1-hexynyloxy group, a 2-hexynyloxy group, a 3-hexynyloxy group,a 4-hexynyloxy group, or a 5-hexynyloxy group; and is preferably a1-propynyloxy group, a 2-propynyloxy group, a 1-butynyloxy group, a2-butynyloxy group, or a 3-butynyloxy group.

The term “may be substituted” in the “C₁-C₆ alkoxy C₁-C₆ alkoxy groupwhich may be substituted with one group or more than one group selectedfrom substituent group β”, the “C₁-C₆ alkenyloxy group which may besubstituted with one group or more than one group selected fromsubstituent group β”, and the “C₁-C₆ alkynyloxy group which may besubstituted with one group or more than one group selected fromsubstituent group β” means unsubstituted or mono- to tri-substituted.

The “C₃-C₁₀ cycloalkyloxy group” in the definitions of substituentgroups α and β is the above-mentioned C₃-C₁₀ cycloalkyl group to whichan oxygen atom is bound and can be, for example, a cyclopropoxy group, acyclobutoxy group, a cyclopentyloxy group, or a cyclohexyloxy group; andis preferably a cyclopropoxy group, a cyclobutoxy group, or acyclopentyloxy group.

The “3- to 6-membered heterocyclyloxy group” in the definition ofsubstituent group α is a cyclic group containing a nitrogen atom, anoxygen atom, and/or a sulfur atom and having 3 to 6 carbon atoms, towhich an oxygen atom is bound; and can be, for example, an aziridinyloxygroup, an azetidinyloxy group, a pyrrolidinyloxy group, a piperidinyloxygroup, a thiranyloxy group, a thienyloxy group, a tetrahydrothienyloxygroup, a tetrahydrothiopyranyloxy group, an oxiranyloxy group, anoxetanyloxy group, a tetrahydrofuryloxy group, or a tetrahydropyranyloxygroup; and is preferably a tetrahydrofuryloxy group or atetrahydropyranyloxy group.

The C₆-C₁₀ aryloxy group of the “C₆-C₁₀ aryloxy group which may besubstituted with one group or more than one group selected fromsubstituent group γ” in the definitions of substituent groups α and β isthe above-mentioned C₆-C₁₀ aryl group to which an oxygen atom is boundand can be, for example, a phenoxy group, an indenyloxy group, or anaphthyloxy group, and is preferably a phenoxy group.

The term “may be substituted” in the above “C₆-C₁₀ aryloxy group whichmay be substituted with one group or more than one group selected fromsubstituent group γ” means unsubstituted or mono- to tri-substituted.

The “C₁-C₆ alkyleneoxy group” in the definitions of substituent groups αand γ can be, for example, a methyleneoxy group, an ethyleneoxy group, atrimethyleneoxy group, a tetramethyleneoxy group, a pentamethyleneoxygroup, or a hexamethyleneoxy group; and is preferably an ethyleneoxygroup or a trimethyleneoxy group.

The “C₁-C₆ alkylenedioxy group” in the definitions of substituent groupsα and γ can be, for example, a methylenedioxy group, an ethylenedioxygroup, a trimethylenedioxy group, a tetramethylenedioxy group, apentamethylenedioxy group, or a hexamethylenedioxy group; and ispreferably a methylenedioxy group or an ethylenedioxy group.

The C₁-C₆ alkylthio group of the “C₁-C₆ alkylthio group which may besubstituted with one group or more than one group selected fromsubstituent group β” in the definition of substituent group α is theabove-mentioned C₁-C₆ alkyl group to which a sulfur atom is bound, andis preferably a methylthio group, an ethylthio group, a propylthiogroup, an isopropylthio group, or a butylthio group, and more preferablya methylthio group or an ethylthio group.

The term “may be substituted” in the above “C₁-C₆ alkylthio group whichmay be substituted with one group or more than one group selected fromsubstituent group β” means unsubstituted or mono- to tri-substituted.

The “C₁-C₆ haloalkylthio group” in the definition of substituent group αis the above-mentioned C₁-C₆ alkylthio group substituted with as manyhalogen atoms as possible and can be, for example, a fluoromethylthiogroup, a difluoromethylthio group, a trifluoromethylthio group, afluoroethylthio group, a difluoroethylthio group, a trifluoroethylthiogroup, a fluoropropylthio group, a difluoropropylthio group, atrifluoropropylthio group, a fluorobutylthio group, a difluorobutylthiogroup, a trifluorobutylthio group, a fluoropentylthio group, adifluoropentylthio group, a trifluoropentylthio group, a fluorohexylthiogroup, a difluorohexylthio group, a trifluorohexylthio group, apentafluoroethylthio group, a hexafluoropropylthio group, anonafluorobutylthio group, a chloromethylthio group, adichloromethylthio group, a trichloromethylthio group, a chloroethylthiogroup, a dichloroethylthio group, a trichloroethylthio group, achloropropylthio group, a dichloropropylthio group, atrichloropropylthio group, a chlorobutylthio group, a dichlorobutylthiogroup, a trichlorobutylthio group, a chloropentylthio group, adichloropentylthio group, a trichloropentylthio group, a chlorohexylthiogroup, a dichlorohexylthio group, a trichlorohexylthio group, apentachloroethylthio group, a hexachloropropylthio group, or anonachlorobutylthio group; and is preferably a fluoromethylthio group, adifluoromethylthio group, a trifluoromethylthio group, a fluoroethylthiogroup, a difluoroethylthio group, a trifluoroethylthio group, afluoropropylthio group, a difluoropropylthio group, or atrifluoropropylthio group.

The C₁-C₆ alkylsulfonyl group of the “C₁-C₆ alkylsulfonyl group whichmay be substituted with one group or more than one group selected fromsubstituent group β” in the definition of substituent group α is theabove-mentioned C₁-C₆ alkyl group to which a sulfonyl group is bound andis preferably a methylsulfonyl group, an ethylsulfonyl group, apropylsulfonyl group, an isopropylsulfonyl group, or a butylsulfonylgroup, and more preferably a methylsulfonyl group or an ethylsulfonylgroup.

The term “may be substituted” in the “C₁-C₆ alkylsulfonyl group whichmay be substituted with one group or more than one group selected fromsubstituent group β” means unsubstituted or mono- to tri-substituted.

The “C₁-C₆ haloalkylsulfonyl group” in the definition of substituentgroup α is the above-mentioned C₁-C₆ alkylsulfonyl group substitutedwith as many halogen atoms as possible and can be, for example, afluoromethylsulfonyl group, a difluoromethylsulfonyl group, atrifluoromethylsulfonyl group, a fluoroethylsulfonyl group, adifluoroethylsulfonyl group, a trifluoroethylsulfonyl group, afluoropropylsulfonyl group, a difluoropropylsulfonyl group, atrifluoropropylsulfonyl group, a fluorobutylsulfonyl group, adifluorobutylsulfonyl group, a trifluorobutylsulfonyl group, afluoropentylsulfonyl group, a difluoropentylsulfonyl group, atrifluoropentylsulfonyl group, a fluorohexylsulfonyl group, adifluorohexylsulfonyl group, a trifluorohexylsulfonyl group, apentafluoroethylsulfonyl group, a hexafluoropropylsulfonyl group, anonafluorobutylsulfonyl group, a chloromethylsulfonyl group, adichloromethylsulfonyl group, a trichloromethylsulfonyl group, achloroethylsulfonyl group, a dichloroethylsulfonyl group, atrichloroethylsulfonyl group, a chloropropylsulfonyl group, adichloropropylsulfonyl group, a trichloropropylsulfonyl group, achlorobutylsulfonyl group, a dichlorobutylsulfonyl group, atrichlorobutylsulfonyl group, a chloropentylsulfonyl group, adichloropentylsulfonyl group, a trichloropentylsulfonyl group, achlorohexylsulfonyl group, a dichlorohexylsulfonyl group, atrichlorohexylsulfonyl group, a pentachloroethylsulfonyl group, ahexachloropropylsulfonyl group, or a nonachlorobutylsulfonyl group; andis preferably a fluoromethylsulfonyl group, a difluoromethylsulfonylgroup, a trifluoromethylsulfonyl group, a fluoroethylsulfonyl group, adifluoroethylsulfonyl group, a trifluoroethylsulfonyl group, afluoropropylsulfonyl group, a difluoropropylsulfonyl group, or atrifluoropropylsulfonyl group.

The C₁-C₆ alkylcarbonyl group of the “C₁-C₆ alkylcarbonyl group whichmay be substituted with one group or more than one group selected fromsubstituent group β” in the definition of substituent group α is theabove-mentioned C₁-C₆ alkyl group to which a carbonyl group is bound andcan be, for example, an acetyl group, an ethylcarbonyl group, apropylcarbonyl group, a butylcarbonyl group, a pentylcarbonyl group, ora hexylcarbonyl group; and is preferably an acetyl group, anethylcarbonyl group, or a propylcarbonyl group.

The term “may be substituted” in the above “C₁-C₆ alkylcarbonyl groupwhich may be substituted with one group or more than one group selectedfrom substituent group β” means unsubstituted or mono- totri-substituted.

The “C₁-C₆ haloalkylcarbonyl group” in the definition of substituentgroup α is the above-mentioned C₁-C₆ haloalkyl group to which a carbonylgroup is bound and can be, for example, a fluoromethylcarbonyl group, adifluoromethylcarbonyl group, a trifluoromethylcarbonyl group, afluoroethylcarbonyl group, a difluoroethylcarbonyl group, atrifluoroethylcarbonyl group, a fluoropropylcarbonyl group, adifluoropropylcarbonyl group, a trifluoropropylcarbonyl group, afluorobutylcarbonyl group, a difluorobutylcarbonyl group, atrifluorobutylcarbonyl group, a fluoropentylcarbonyl group, adifluoropentylcarbonyl group, a trifluoropentylcarbonyl group, afluorohexylcarbonyl group, a difluorohexylcarbonyl group, atrifluorohexylcarbonyl group, a pentafluoroethylcarbonyl group, ahexafluoropropylcarbonyl group, a nonafluorobutylcarbonyl group, achloromethylcarbonyl group, a dichloromethylcarbonyl group, atrichloromethylcarbonyl group, a chloroethylcarbonyl group, adichloroethylcarbonyl group, a trichloroethylcarbonyl group, achloropropylcarbonyl group, a dichloropropylcarbonyl group, atrichloropropylcarbonyl group, a chlorobutylcarbonyl group, adichlorobutylcarbonyl group, a trichlorobutylcarbonyl group, achloropentylcarbonyl group, a dichloropentylcarbonyl group, atrichloropentylcarbonyl group, a chlorohexylcarbonyl group, adichlorohexylcarbonyl group, a trichlorohexylcarbonyl group, apentachloroethylcarbonyl group, a hexachloropropylcarbonyl group, or anonachlorobutylcarbonyl group; and is preferably a fluoromethylcarbonylgroup, a difluoromethylcarbonyl group, a trifluoromethylcarbonyl group,a fluoroethylcarbonyl group, a difluoroethylcarbonyl group, atrifluoroethylcarbonyl group, a fluoropropylcarbonyl group, adifluoropropylcarbonyl group, or a trifluoropropylcarbonyl group.

The C₆-C₁₀ arylcarbonyl group of the “C₆-C₁₀ arylcarbonyl group whichmay be substituted with one group or more than one group selected fromsubstituent group γ” in the definition of substituent group α is theabove-mentioned C₆-C₁₀ aryl group to which a carbonyl group is bound andcan be, for example, a benzoyl group, an indenylcarbonyl group, or anaphthylcarbonyl group and is preferably a benzoyl group.

The term “may be substituted” in the above “C₆-C₁₀ arylcarbonyl groupwhich may be substituted with one group or more than one group selectedfrom substituent group γ” means unsubstituted or mono- totri-substituted.

The “C₁-C₆ alkoxycarbonyl group” in the definition of substituent groupβ is the above-mentioned C₁-C₆ alkoxy group to which a carbonyl group isbound and can be, for example, a linear or branched alkoxycarbonyl grouphaving 1 to 6 carbon atoms; and is preferably a methoxycarbonyl group,an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonylgroup, or a butoxycarbonyl group; and more preferably a methoxycarbonylgroup or an ethoxycarbonyl group.

The “N—C₆-C₁₀ arylacetamido group” in the definition of substituentgroup β is an acetamido group having the above-mentioned C₆-C₁₀ arylgroup on the nitrogen atom and can be, for example, an N-phenylacetamidogroup, an N-indenylacetamido group, or an N-naphthylacetamido group andis preferably an N-phenylacetamido group.

The “C₁-C₆ alkoxycarbonylamido group” in the definition of substituentgroup β is the above-mentioned C₁-C₆ alkoxycarbonyl group having acarbonyl group to which an amino group is bound and can be, for example,a linear or branched alkoxycarbonylamido group having 1 to 6 carbonatoms, and is preferably a methoxycarbonylamido group, anethoxycarbonylamido group, a propoxycarbonylamido group, anisopropoxycarbonylamido group, or a butoxycarbonylamido group, and morepreferably a methoxycarbonylamido group or an ethoxycarbonylamido group.

The “C₂-C₆ cyclic amino group” in the definition of substituent group γcan be, for example, an aziridine group, an azetidine group, apyrrolidine group, or a piperidine group and is preferably a pyrrolidinegroup or a piperidine group.

In the compounds having Formula (I) according to the present invention,R¹ is preferably a phenyl group which may be substituted with one groupor more than one group selected from substituent group α or a pyridylgroup which may be substituted with one group or more than one groupselected from substituent group α; more preferably a phenyl group whichmay be substituted with one group or more than one group selected fromsubstituent group α; still more preferably a phenyl group substitutedwith any one group selected from the group consisting of C₁-C₆ alkoxygroups which may be substituted with one group or more than one groupselected from substituent group β, C₆-C₁₀ aryloxy groups which may besubstituted with one group or more than one group selected fromsubstituent group γ, and C₁-C₆ haloalkoxy groups; and particularly stillmore preferably a 4-isobutyloxyphenyl group, a4-(cyclopropylmethoxy)phenyl group, a 4-(2-cyclopropylethoxy)phenylgroup, a 4-(1-methylcyclopropylmethoxy)phenyl group, a4-(3,3,3-trifluoropropyloxy)phenyl group, a4-(4,4,4-trifluorobutyloxy)phenyl group, a 4-(2-phenylethoxy)phenylgroup, a 4-(2-(4-methoxyphenyl)ethoxy)phenyl group, a4-(2-(3-methoxyphenyl)ethoxy)phenyl group, a4-(2-(4-chlorophenyl)ethoxy)phenyl group, a4-(2-(4-(N,N-dimethylamino)phenyl)ethoxy)phenyl group, a4-(4-chlorophenoxy)phenyl group, or a 4-(4-trifluoromethylphenoxy)phenylgroup.

R² is preferably a C₆-C₁₀ aryl group which may be substituted with onegroup or more than one group selected from substituent group α; morepreferably a phenyl group which may be substituted with one group ormore than one group selected from substituent group α; still morepreferably a phenyl group substituted with any one group selected fromthe group consisting of halogen atoms, C₁-C₆ alkyl groups, C₁-C₆haloalkyl groups, C₃-C₆ cycloalkyl groups, C₁-C₆ alkoxy groups, C₃-C₆cycloalkyloxy groups, C₁-C₆ haloalkoxy groups, C₁-C₆ alkylthio groups,and 5- to 10-membered heteroaryl groups; and particularly still morepreferably a 4-fluorophenyl group, a 4-chlorophenyl group, a4-trifluoromethylphenyl group, a 4-isopropylphenyl group, a4-cyclopropylphenyl group, a 4-isopropyloxyphenyl group, a4-difluoromethoxyphenyl group, a 4-trifluoromethoxyphenyl group, a4-(2,2,2-trifluoroethoxy)phenyl group, a 4-(2,2-difluoroethoxy)phenylgroup, a 4-cyclopropyloxyphenyl group, a 4-ethoxyphenyl group, a4-methylthiophenyl group, or a 4-(1H-pyrrol-1-yl)phenyl group.

X is preferably a group having the formula N(R³)R⁴ wherein R⁴ is ahydrogen atom, and R³ is a C₁-C₆ haloalkyl group, a C₁-C₆ alkyl groupwhich may be substituted with one group or more than one group selectedfrom substituent group β, or a C₁-C₆ hydroxyalkyl group which may beprotected by a hydroxyl protecting group; more preferably a group havingthe formula N(R³)R⁴ wherein R⁴ is a hydrogen atom, and R³ is a C₂-C₃haloalkyl group, a C₂-C₃ hydroxyalkyl group which may be protected by ahydroxyl protecting group, or a C₁-C₃ alkyl group substituted with a1-hydroxycyclopropyl group; and still more preferably a2-fluoroethylamino group, a 2,2-difluoroethylamino group, a2-hydroxyethylamino group, a 1-(2-hydroxypropyl)amino group, a1-hydroxycyclopropylmethylamino group, a 2-acetoxyethylamino group, a2-(morpholin-4-ylacetoxy)ethylamino group, or a2-(3-carboxypropionyloxy)ethylamino group.

In the compounds having Formula (I′) according to the present invention,R⁵ is preferably any one group selected from the group consisting ofhalogen atoms, C₁-C₆ alkyl groups which may be substituted with onegroup or more than one group selected from substituent group β, C₁-C₆haloalkyl groups, C₃-C₆ cycloalkyl groups, C₁-C₆ alkoxy groups which maybe substituted with one group or more than one group selected fromsubstituent group β, C₆-C₁₀ aryloxy groups which may be substituted withone group or more than one group selected from substituent group γ,C₁-C₆ haloalkoxy groups, and C₃-C₆ cycloalkyloxy groups; more preferablyany one group selected from the group consisting of C₁-C₆ alkoxy groupswhich may be substituted with one group or more than one group selectedfrom substituent group β, C₆-C₁₀ aryloxy groups which may be substitutedwith one group or more than one group selected from substituent group γ,and C₁-C₆ haloalkoxy groups; and still more preferably an isobutyloxygroup, a cyclopropylmethoxy group, a 2-cyclopropylethoxy group, a1-methylcyclopropylmethoxy group, a 3,3,3-trifluoropropyloxy group, a4,4,4-trifluorobutyloxy group, a 2-phenylethoxy group, a2-(4-methoxyphenyl)ethoxy group, a 2-(3-methoxyphenyl)ethoxy group, a2-(4-chlorophenyl)ethoxy group, a 2-(4-(N,N-dimethylamino)phenyl)ethoxygroup, a 4-chlorophenoxy group, or a 4-trifluoromethylphenoxy group.

R⁶ is preferably any one group selected from the group consisting ofhalogen atoms, C₁-C₆ alkyl groups, C₁-C₆ haloalkyl groups, C₃-C₆cycloalkyl groups, C₁-C₆ alkoxy groups, C₃-C₆ cycloalkyloxy groups,C₁-C₆ haloalkoxy groups, C₁-C₆ alkylthio groups, and 5- to 10-memberedheteroaryl groups; more preferably a fluorine atom, a chlorine atom, atrifluoromethyl group, an isopropyl group, a cyclopropyl group, anisopropyloxy group, a difluoromethoxy group, a trifluoromethoxy group, a2,2,2-trifluoroethoxy group, a 2,2-difluoroethoxy group, acyclopropyloxy group, an ethoxy group, a methylthio group, or a1H-pyrrol-1-yl group; and still more preferably an ethoxy group, atrifluoromethyl group, a cyclopropyl group, a cyclopropyloxy group, adifluoromethoxy group, a trifluoromethoxy group, or a 2,2-difluoroethoxygroup.

R⁷ is preferably a C₁-C₆ haloalkyl group, a C₁-C₆ alkyl group which maybe substituted with one group or more than one group selected fromsubstituent group β, or a C₁-C₆ hydroxyalkyl group which may beprotected by a hydroxyl protecting group; more preferably a C₂-C₃haloalkyl group, a C₂-C₃ hydroxyalkyl group which may be protected by ahydroxyl protecting group, or a C₁-C₃ alkyl group substituted with1-hydroxycyclopropyl; and still more preferably a 2-fluoroethyl group, a2,2-difluoroethyl group, a 2-hydroxyethyl group, a 2-hydroxypropylgroup, a 1-hydroxycyclopropylmethyl group, a 2-acetoxyethyl group, a2-(morpholin-4-ylacetoxy)ethyl group, or a2-(3-carboxypropionyloxy)ethyl group.

In preferred combinations of substituents of a compound having Formula(I′) according to the present invention, R⁵ is any one group selectedfrom the group consisting of halogen atoms, C₁-C₆ alkyl groups which maybe substituted with one group or more than one group selected fromsubstituent group β, C₁-C₆ haloalkyl groups, C₃-C₆ cycloalkyl groups,C₁-C₆ alkoxy groups which may be substituted with one group or more thanone group selected from substituent group β, C₆-C₁₀ aryloxy groups whichmay be substituted with one group or more than one group selected fromsubstituent group γ, C₁-C₆ haloalkoxy groups, and C₃-C₆ cycloalkyloxygroups; R⁶ is any one group selected from the group consisting ofhalogen atoms, C₁-C₆ alkyl groups, C₁-C₆ haloalkyl groups, C₃-C₆cycloalkyl groups, C₁-C₆ alkoxy groups, C₃-C₆ cycloalkyloxy groups,C₁-C₆ haloalkoxy groups, C₁-C₆ alkylthio groups, and 5- to 10-memberedheteroaryl groups; and R⁷ is a C₁-C₆ haloalkyl group, a C₁-C₆ alkylgroup which may be substituted with one group or more than one groupselected from substituent group β, or a C₁-C₆ hydroxyalkyl group whichmay be protected by a hydroxyl protecting group. In more preferredcombinations of substituents, R⁵ is any one group selected from thegroup consisting of C₁-C₆ alkoxy groups which may be substituted withone group or more than one group selected from substituent group β,C₆-C₁₀ aryloxy groups which may be substituted with one group or morethan one group selected from substituent group γ, and C₁-C₆ haloalkoxygroups; R⁶ is a fluorine atom, a chlorine atom, a trifluoromethyl group,an isopropyl group, a cyclopropyl group, an isopropyloxy group, adifluoromethoxy group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxygroup, a 2,2-difluoroethoxy group, a cyclopropyloxy group, an ethoxygroup, a methylthio group, or a 1H-pyrrol-1-yl group; and R⁷ is a C₂-C₃haloalkyl group, a C₂-C₃ hydroxyalkyl group which may be protected by ahydroxyl protecting group, or a C₁-C₃ alkyl group substituted with1-hydroxycyclopropyl. In still more preferred combinations ofsubstituents, R⁵ is an isobutyloxy group, a cyclopropylmethoxy group, a2-cyclopropylethoxy group, a 1-methylcyclopropylmethoxy group, a3,3,3-trifluoropropyloxy group, a 4,4,4-trifluorobutyloxy group, a2-phenylethoxy group, a 2-(4-methoxyphenyl)ethoxy group, a2-(3-methoxyphenyl)ethoxy group, a 2-(4-chlorophenyl)ethoxy group, a2-(4-(N,N-dimethylamino)phenyl)ethoxy group, a 4-chlorophenoxy group, ora 4-trifluoromethylphenoxy group; R⁶ is an ethoxy group, atrifluoromethyl group, a cyclopropyl group, a cyclopropyloxy group, adifluoromethoxy group, a trifluoromethoxy group, or a 2,2-difluoroethoxygroup; and R⁷ is a 2-fluoroethyl group, a 2,2-difluoroethyl group, a2-hydroxyethyl group, a 2-hydroxypropyl group, a1-hydroxycyclopropylmethyl group, a 2-acetoxyethyl group, a2-(morpholin-4-ylacetoxy)ethyl group, or a2-(3-carboxypropionyloxy)ethyl group.

The compounds having Formula (I′) according to the present invention arepreferably:

-   4-(2-cyclopropylethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(2-cyclopropylethoxy)-N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(2-cyclopropylethoxy)-N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(2-cyclopropylethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   4-(2-cyclopropylethoxy)-N-(2-[4-(2,2-difluoroethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(2-cyclopropylethoxy)-N-(2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   2-{[(2Z)-2-{[4-(2-cyclopropylethoxy)benzoyl]amino}-3-(4-cyclopropylphenyl)propen-2-oyl]amino}ethyl    acetate,-   2-{[(2Z)-2-{[4-(2-cyclopropylethoxy)benzoyl]amino}-3-(4-cyclopropylphenyl)propen-2-oyl]amino}ethyl    succinate,-   4-(2-cyclopropylethoxy)-N    {1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,-   4-(2-cyclopropylethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(1H-pyrrol-1-yl)phenyl]vinyl}benzamide,-   N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-cyclopropylethoxy)benzamide,-   N-[1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   N-(2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(methylthio)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-[1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide,-   4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   N-(2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(4,4,4-trifluorobutoxy)benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(4,4,4-trifluorobutoxy)benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-{1-{[(2,2-difluoroethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-{1-({[(2S)-2-hydroxypropyl]amino}carbonyl)-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[4-(trifluoromethyl)phenoxy]benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide,-   4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,    and-   4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide;

more preferably:

-   4-(2-cyclopropylethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(2-cyclopropylethoxy)-N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(2-cyclopropylethoxy)-N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(2-cyclopropylethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   4-(2-cyclopropylethoxy)-N-(2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   2-{[(2Z)-2-{[4-(2-cyclopropylethoxy)benzoyl]amino}-3-(4-cyclopropylphenyl)propen-2-oyl]amino}ethyl    acetate,-   4-(2-cyclopropylethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,-   N-(2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-cyclopropylethoxy)benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   N-(2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   4-[2-(4-chlorophenyl)ethoxy]-N-(2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(4,4,4-trifluorobutoxy)benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(4,4,4-trifluorobutoxy)benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-{1-{[(2,2-difluoroethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-{1-({[(2S)-2-hydroxypropyl]amino}carbonyl)-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[4-(trifluoromethyl)phenoxy]benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide,-   N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide,-   4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,    and-   4-(4-chlorophenoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide.

The term “bone metabolic disease” in the present invention meansdiseases characterized by a substantial decrease in bone mass or anincrease in blood calcium concentration and diseases that requiresuppression of the bone resorption or the rate of bone resorption fortheir prophylaxis or treatment.

Examples of such bone metabolic disease include osteoporosis,hypercalcemia, bone metastasis of cancer, periodontal diseases, bonePaget's disease, and osteoarthrosis.

The above term “osteoporosis” means a systemic disease in which, due toa decrease in bone mass, the bone microarchitecture is disrupted and themechanical strength of bone is reduced, resulting in an increased riskof fractures. Examples of osteoporosis include postmenopausalosteoporosis, senile osteoporosis, secondary osteoporosis caused bysteroid or immunosuppressive agent use, osteoclasis or osteopenia due torheumatoid arthritis, and osteopenia due to artificial jointreplacement.

The above term “treatment” means to cure or improve a disease or asymptom or to suppress a symptom.

The above term “significantly decrease blood calcium concentration”generally means to decrease the blood calcium concentration that isstrictly maintained at a constant value to a level lower than a generallevel. The decrease ratio is preferably 0.1% or more, more preferably0.5% or more, still more preferably 1% or more, and particularly morepreferably 5% or more.

The above term “its pharmacologically acceptable salt” means a basicsalt or an acid salt produced by a reaction of a compound having Formula(I) of the present invention, when the compound has an acidic group or abasic group, with a base or an acid.

The pharmacologically acceptable “basic salt” of the compound havingFormula (I) of the present invention is preferably an alkali metal saltsuch as a sodium salt, a potassium salt, or a lithium salt; analkaline-earth metal salt such as a magnesium salt or a calcium salt; anorganic basic salt such as an N-methylmorpholine salt, a triethylaminesalt, a tributylamine salt, a diisopropylethylamine salt, adicyclohexylamine salt, an N-methylpiperidine salt, a pyridine salt, a4-pyrrolidinopyridine salt, or a picoline salt; or an amino acid saltsuch as a glycine salt, a lysine salt, an alginine salt, an ornithinesalt, a glutamic acid salt, or an aspartic acid salt, and preferably analkali metal salt.

The pharmacologically acceptable “acid salt” of the compound havingFormula (I) of the present invention is preferably an inorganic acidsalt, for example, a hydrohalide such as hydrofluoride, hydrochloride,hydrobromide, or hydroiodide, a nitrate, a perchlorate, a sulfate, or aphosphate; an organic acid salt, for example, a lower alkanesulfonatesuch as a methanesulfonate, a trifluoromethanesulfonate, or anethanesulfonate, an arylsulfonate such as a benzenesulfonate or ap-toluenesulfonate, an acetate, a malate, a fumarate, a succinate, acitrate, an ascorbate, a tartrate, an oxalate, or a maleate; or an aminoacid salt such as a glycine salt, a lysine salt, an alginine salt, anornithine salt, a glutamic acid salt, or an aspartic acid salt, and mostpreferably a hydrohalide.

The compound having Formula (I) or a pharmacologically acceptable saltthereof of the present invention may become a hydrate by absorbing wateror being attached with water when the salt is left in the air orrecrystallized, and such a hydrate is included in the present invention.

The compound having Formula (I) or a pharmacologically acceptable saltthereof of the present invention has an acrylamide structure in itsmolecule and thereby can be present in two regioisomers, namely,(E)-isomer and (Z)-isomer, due to the double bond. In the compoundaccording to the present invention, both these regioisomers and mixturesthereof are represented by a single Formula (I). Therefore, the presentinvention includes both these regioisomers and mixtures containing theregioisomers at any proportion and preferably includes mainly the(Z)-isomer. The isomers of the mixtures can be separated by a knownseparation method.

The compound having Formula (I) or a pharmacologically acceptable saltthereof of the present invention has optical isomers when it has anasymmetric carbon atom in its molecule. In the compound according to thepresent invention, all optical isomers and mixtures thereof arerepresented by a single Formula (I). Therefore, the present inventionincludes all these optical isomers and mixtures containing the opticalisomers at any proportion.

The compounds having Formula (I) of the present invention which havebeen labeled with an isotope (for example, ³H, ¹⁴C, or ³⁵S) are alsoincluded in the present invention.

Preferred examples of the compound having Formula (I) of the presentinvention are compounds having Formula (I-1), (I-2), or (I-3) describedin the following Tables 1, 2, and 3, but the present invention is notlimited to these compounds.

In the Tables, substituents are denoted by the following abbreviations.In a substituent represented by a plurality of abbreviations, thesubstituent consists of the substituents denoted by the abbreviationsbound to each other. For example, 2-cPrEtO denotes a 2-cyclopropylethoxygroup.

di di Me methyl group Et ethyl group Pr propyl group cPr cyclopropylgroup iPr isopropyl group cBu cyclobutyl group iBu isobutyl group tButertiary butyl group Pn pentyl group cPn cyclopentyl group cHxcyclohexyl group cHp cycloheptyl group Ph phenyl group diEtNdiethylamino group diMeN dimethylamino group Thi thiophen-2-yl groupPyrr pyrrol-1-yl group Ind inden-2-yl group 1-cPen cyclopenten-1-ylgroup 2-cPen cyclopenten-2-yl group αNp naphthalen-1-yl group βNpnaphthalen-2-yl group Ac acetyl group Ada adamantyl group Bn benzylgroup Boc t-butoxycarbonyl group Bun 3-buten-1-yl group Bz benzoyl groupBDO 2-benzo[1,3]dioxol-5-yl group CF₃Pr 4,4,4-trifluorobutyl groupCF₃CF₂Pr 4,4,5,5,5-pentafluoropentanyl group Chr2,2-dimethylchroman-6-yl group DDQZ2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl group 2-DHBD2,3-dihydrobenzo[1,4]dioxin-2-yl group 6-DHBD2,3-dihydrobenzo[1,4]dioxin-6-yl group MEDO methylenedioxy group Furfuran-2-yl group Mor morpholin-4-yl group Phtl phthaloyl group Pippiperidin-4-yl group Piz piperazin-1-yl group Pre 2-propen-1-yl groupPry 2-propyn-1-yl group Phthiz benzothiazol-2-yl group 2-Py pyridin-2-ylgroup 3-Py pyridin-3-yl group 4-Py pyridin-4-yl group Pyrdpyrrolidin-1-yl group DOPyrd 2,5-dioxopyrrolidin-1-yl group Pyrrpyrrol-1-yl group Quin quinolin-3-yl group THF tetrahydrofuran-2-ylgroup THP tetrahydropyran-4-yl group Triz triazol-1-yl group

TABLE 1 Exemplary compound table 1 (I-1)

Compound No. R^(a) R^(b) 1-1 iBuO EtO 1-2 iBuO iPrO 1-3 iBuO cPrO 1-4iBuO CHF₂O 1-5 iBuO CF₃O 1-6 iBuO CH₂FCH₂O 1-7 iBuO CHF₂CH₂O 1-8 iBuOCF₃CH₂O 1-9 iBuO CHF₂CF₂O 1-10 iBuO Et 1-11 iBuO iPr 1-12 iBuO cPr 1-13iBuO CF₃ 1-14 iBuO 1-cPen 1-15 iBuO MeS 1-16 iBuO EtS 1-17 iBuO CF₃S1-18 iBuO Pyrr 1-19 iBuO Ph 1-20 iBuO H 1-21 iBuO F 1-22 iBuO NO₂ 1-23iBuO CN 1-24 iBuO iBu 1-25 iBuO Ac 1-26 iBuO cHx 1-27 iBuO tBu 1-28 iBuO4-FPh 1-29 iBuO 4-Py 1-30 iBuO 3-Py 1-31 iBuO 2-Py 1-32 iBuO Triz 1-33iBuO AcNH 1-34 iBuO diMeN 1-35 iBuO diEtN 1-36 iBuO Mor 1-37 iBuO2,5-diMePyrr 1-38 iBuO MeSO₂ 1-39 iBuO HO 1-40 iBuO MeO 1-41 iBuO PhO1-42 iBuO cBuO 1-43 iBuO cPnO 1-44 iBuO cHxO 1-45 iBuO cHpO 1-46 iBuOcHxMeO 1-47 iBuO PrO 1-48 iBuO tBuO 1-49 iBuO iBuO 1-50 iBuO cPrMeO 1-51iBuO 1-cPrEtO 1-52 iBuO di(CH₂F)CHO 1-53 iBuO 1-CF₃EtO 1-54 iBuO2-CF₃EtO 1-55 iBuO BnO 1-56 iBuO Cl 1-57 iBuO Br 1-58 2-cPrEtO EtO 1-592-cPrEtO iPrO 1-60 2-cPrEtO cPrO 1-61 2-cPrEtO CHF₂O 1-62 2-cPrEtO CF₃O1-63 2-cPrEtO CH₂FCH₂O 1-64 2-cPrEtO CHF₂CH₂O 1-65 2-cPrEtO CF₃CH₂O 1-662-cPrEtO Et 1-67 2-cPrEtO iPr 1-68 2-cPrEtO cPr 1-69 2-cPrEtO CF₃ 1-702-cPrEtO 1-cPen 1-71 2-cPrEtO MeS 1-72 2-cPrEtO Pyrr 1-73 2-cPrEtO Ph1-74 2-cPrEtO H 1-75 2-cPrEtO F 1-76 2-cPrEtO NO₂ 1-77 2-cPrEtO CN 1-782-cPrEtO iBu 1-79 2-cPrEtO Ac 1-80 2-cPrEtO cHx 1-81 2-cPrEtO tBu 1-822-cPrEtO 4-FPh 1-83 2-cPrEtO 4-Py 1-84 2-cPrEtO 3-Py 1-85 2-cPrEtO 2-Py1-86 2-cPrEtO Triz 1-87 2-cPrEtO AcNH 1-88 2-cPrEtO diMeN 1-89 2-cPrEtOdiEtN 1-90 2-cPrEtO Mor 1-91 2-cPrEtO 2,5-diMePyrr 1-92 2-cPrEtO MeSO₂1-93 2-cPrEtO HO 1-94 2-cPrEtO MeO 1-95 2-cPrEtO PhO 1-96 2-cPrEtO cBuO1-97 2-cPrEtO cPnO 1-98 2-cPrEtO cHxO 1-99 2-cPrEtO cHpO 1-100 2-cPrEtOcHxMeO 1-101 2-cPrEtO PrO 1-102 2-cPrEtO tBuO 1-103 2-cPrEtO iBuO 1-1042-cPrEtO cPrMeO 1-105 2-cPrEtO 1-cPrEtO 1-106 2-cPrEtO di(CH₂F)CHO 1-1072-cPrEtO 1-CF₃EtO 1-108 2-cPrEtO BnO 1-109 2-cPrEtO Cl 1-110 2-cPrEtO Br1-111 2-PhEtO EtO 1-112 2-PhEtO iPrO 1-113 2-PhEtO cPrO 1-114 2-PhEtOCHF₂O 1-115 2-PhEtO CF₃O 1-116 2-PhEtO CH₂FCH₂O 1-117 2-PhEtO CHF₂CH₂O1-118 2-PhEtO CF₃CH₂O 1-119 2-PhEtO Et 1-120 2-PhEtO iPr 1-121 2-PhEtOcPr 1-122 2-PhEtO CF₃ 1-123 2-PhEtO 1-cPen 1-124 2-PhEtO MeS 1-1252-PhEtO Pyrr 1-126 2-PhEtO Ph 1-127 2-PhEtO Cl 1-128 2-(4-MeOPh)EtO EtO1-129 2-(4-MeOPh)EtO iPrO 1-130 2-(4-MeOPh)EtO cPrO 1-131 2-(4-MeOPh)EtOCHF₂O 1-132 2-(4-MeOPh)EtO CF₃O 1-133 2-(4-MeOPh)EtO CH₂FCH₂O 1-1342-(4-MeOPh)EtO CHF₂CH₂O 1-135 2-(4-MeOPh)EtO CF₃CH₂O 1-1362-(4-MeOPh)EtO Et 1-137 2-(4-MeOPh)EtO iPr 1-138 2-(4-MeOPh)EtO cPr1-139 2-(4-MeOPh)EtO CF₃ 1-140 2-(4-MeOPh)EtO 1-cPen 1-1412-(4-MeOPh)EtO MeS 1-142 2-(4-MeOPh)EtO Pyrr 1-143 2-(4-MeOPh)EtO Ph1-144 2-(4-MeOPh)EtO Cl 1-145 2-(3-MeOPh)EtO EtO 1-146 2-(3-MeOPh)EtOiPrO 1-147 2-(3-MeOPh)EtO cPrO 1-148 2-(3-MeOPh)EtO CHF₂O 1-1492-(3-MeOPh)EtO CF₃O 1-150 2-(3-MeOPh)EtO CH₂FCH₂O 1-151 2-(3-MeOPh)EtOCHF₂CH₂O 1-152 2-(3-MeOPh)EtO CF₃CH₂O 1-153 2-(3-MeOPh)EtO Et 1-1542-(3-MeOPh)EtO iPr 1-155 2-(3-MeOPh)EtO cPr 1-156 2-(3-MeOPh)EtO CF₃1-157 2-(3-MeOPh)EtO 1-cPen 1-158 2-(3-MeOPh)EtO MeS 1-1592-(3-MeOPh)EtO Pyrr 1-160 2-(3-MeOPh)EtO Ph 1-161 2-(3-MeOPh)EtO Cl1-162 2-(4-diMeNPh)EtO EtO 1-163 2-(4-diMeNPh)EtO iPrO 1-1642-(4-diMeNPh)EtO cPrO 1-165 2-(4-diMeNPh)EtO CHF₂O 1-1662-(4-diMeNPh)EtO CF₃O 1-167 2-(4-diMeNPh)EtO CH₂FCH₂O 1-1682-(4-diMeNPh)EtO CHF₂CH₂O 1-169 2-(4-diMeNPh)EtO CF₃CH₂O 1-1702-(4-diMeNPh)EtO Et 1-171 2-(4-diMeNPh)EtO iPr 1-172 2-(4-diMeNPh)EtOcPr 1-173 2-(4-diMeNPh)EtO CF₃ 1-174 2-(4-diMeNPh)EtO 1-cPen 1-1752-(4-diMeNPh)EtO MeS 1-176 2-(4-diMeNPh)EtO Pyrr 1-177 2-(4-diMeNPh)EtOPh 1-178 2-(4-diMeNPh)EtO Cl 1-179 2-(3-diMeNPh)EtO EtO 1-1802-(3-diMeNPh)EtO iPrO 1-181 2-(3-diMeNPh)EtO cPrO 1-182 2-(3-diMeNPh)EtOCHF₂O 1-183 2-(3-diMeNPh)EtO CF₃O 1-184 2-(3-diMeNPh)EtO CH₂FCH₂O 1-1852-(3-diMeNPh)EtO CHF₂CH₂C 1-186 2-(3-diMeNPh)EtO CF₃CH₂O 1-1872-(3-diMeNPh)EtO Et 1-188 2-(3-diMeNPh)EtO iPr 1-189 2-(3-diMeNPh)EtOcPr 1-190 2-(3-diMeNPh)EtO CF₃ 1-191 2-(3-diMeNPh)EtO 1-cPen 1-1922-(3-diMeNPh)EtO MeS 1-193 2-(3-diMeNPh)EtO Pyrr 1-194 2-(3-diMeNPh)EtOPh 1-195 2-(3-diMeNPh)EtO Cl 1-196 2-(4-ClPh)EtO EtO 1-197 2-(4-ClPh)EtOiPrO 1-198 2-(4-ClPh)EtO cPrO 1-199 2-(4-ClPh)EtO CHF₂O 1-2002-(4-ClPh)EtO CF₃O 1-201 2-(4-ClPh)EtO CH₂FCH₂O 1-202 2-(4-ClPh)EtOCHF₂CH₂O 1-203 2-(4-ClPh)EtO CF₃CH₂O 1-204 2-(4-ClPh)EtO Et 1-2052-(4-ClPh)EtO iPr 1-206 2-(4-ClPh)EtO cPr 1-207 2-(4-ClPh)EtO CF₃ 1-2082-(4-ClPh)EtO 1-cPen 1-209 2-(4-ClPh)EtO MeS 1-210 2-(4-ClPh)EtO Pyrr1-211 2-(4-ClPh)EtO Ph 1-212 2-(4-ClPh)EtO Cl 1-213 2-(4-FPh)EtO EtO1-214 2-(4-FPh)EtO iPrO 1-215 2-(4-FPh)EtO cPrO 1-216 2-(4-FPh)EtO CHF₂O1-217 2-(4-FPh)EtO CF₃O 1-218 2-(4-FPh)EtO CH₂FCH₂O 1-219 2-(4-FPh)EtOCHF₂CH₂O 1-220 2-(4-FPh)EtO CF₃CH₂O 1-221 2-(4-FPh)EtO Et 1-2222-(4-FPh)EtO iPr 1-223 2-(4-FPh)EtO cPr 1-224 2-(4-FPh)EtO CF₃ 1-2252-(4-FPh)EtO 1-cPen 1-226 2-(4-FPh)EtO MeS 1-227 2-(4-FPh)EtO Pyrr 1-2282-(4-FPh)EtO Ph 1-229 2-(4-FPh)EtO Cl 1-230 2-(4-cPrPh)EtO EtO 1-2312-(4-cPrPh)EtO iPrO 1-232 2-(4-cPrPh)EtO cPrO 1-233 2-(4-cPrPh)EtO CHF₂O1-234 2-(4-cPrPh)EtO CF₃O 1-235 2-(4-cPrPh)EtO CH₂FCH₂O 1-2362-(4-cPrPh)EtO CHF₂CH₂O 1-237 2-(4-cPrPh)EtO CF₃CH₂O 1-2382-(4-cPrPh)EtO Et 1-239 2-(4-cPrPh)EtO iPr 1-240 2-(4-cPrPh)EtO cPr1-241 2-(4-cPrPh)EtO CF₃ 1-242 2-(4-cPrPh)EtO 1-cPen 1-2432-(4-cPrPh)EtO MeS 1-244 2-(4-cPrPh)EtO Pyrr 1-245 2-(4-cPrPh)EtO Ph1-246 2-(4-cPrPh)EtO Cl 1-247 cBuMeO EtO 1-248 cBuMeO iPrO 1-249 cBuMeOcPrO 1-250 cBuMeO CHF₂O 1-251 cBuMeO CF₃O 1-252 cBuMeO CH₂FCH₂O 1-253cBuMeO CHF₂CH₂O 1-254 cBuMeO CF₃CH₂O 1-255 cBuMeO Et 1-256 cBuMeO iPr1-257 cBuMeO cPr 1-258 cBuMeO CF₃ 1-259 cBuMeO MeS 1-260 3-cPrPrO EtO1-261 3-cPrPrO iPrO 1-262 3-cPrPrO cPrO 1-263 3-cPrPrO CHF₂O 1-2643-cPrPrO CF₃O 1-265 3-cPrPrO CH₂FCH₂O 1-266 3-cPrPrO CHF₂CH₂O 1-2673-cPrPrO CF₃CH₂O 1-268 3-cPrPrO Et 1-269 3-cPrPrO iPr 1-270 3-cPrPrO cPr1-271 3-cPrPrO CF₃ 1-272 3-cPrPrO MeS 1-273 3-cPrPrO Cl 1-274 2-CF₃EtOiPrO 1-275 2-CF₃EtO cPrO 1-276 2-CF₃EtO CHF₂O 1-277 2-CF₃EtO CF₃O 1-2782-CF₃EtO iPr 1-279 2-CF₃EtO cPr 1-280 2-CF₃EtO CF₃ 1-281 2-CF₃EtO MeS1-282 2-CF₃EtO Cl 1-283 2-ThiEtO iPrO 1-284 2-ThiEtO cPrO 1-285 2-ThiEtOCHF₂O 1-286 2-ThiEtO CF₃O 1-287 2-ThiEtO iPr 1-288 2-ThiEtO cPr 1-2892-ThiEtO CF₃ 1-290 2-ThiEtO MeS 1-291 2-ThiEtO Cl 1-292 2-PyrrEtO iPrO1-293 2-PyrrEtO cPrO 1-294 2-PyrrEtO CHF₂O 1-295 2-PyrrEtO CF₃O 1-2962-PyrrEtO iPr 1-297 2-PyrrEtO cPr 1-298 2-PyrrEtO CF₃ 1-299 2-PyrrEtOMeS 1-300 2-PyrrEtO Cl 1-301 3-PhPrO iPrO 1-302 3-PhPrO iPr 1-3033-PhPrO cPrO 1-304 3-PhPrO cPr 1-305 3-PhPrO CF₃O 1-306 3-PhPrO CF₃1-307 4-PhBuO iPrO 1-308 4-PhBuO iPr 1-309 4-PhBuO cPrO 1-310 4-PhBuOcPr 1-311 4-PhBuO CF₃O 1-312 4-PhBuO CF₃ 1-313 2-PhOEtO iPrO 1-3142-PhOEtO iPr 1-315 2-PhOEtO cPrO 1-316 2-PhOEtO cPr 1-317 2-PhOEtO CF₃O1-318 2-PhOEtO CF₃ 1-319 2-PhOEtO CHF₂O 1-320 2-PhOEtO CHF₂CH₂O 1-3212-PhOEtO MeS 1-322 2-PhOEtO Cl 1-323 3-cPrPrO iPrO 1-324 3-cPrPrO iPr1-325 3-cPrPrO cPrO 1-326 3-cPrPrO cPr 1-327 3-cPrPrO CF₃O 1-3283-cPrPrO CF₃ 1-329 3-cPrPrO CHF₂O 1-330 3-cPrPrO CHF₂CH₂O 1-331 BDOEtOiPrO 1-332 BDOEtO iPr 1-333 BDOEtO cPrO 1-334 BDOEtO cPr 1-335 4-EtPhOiPrO 1-336 4-EtPhO iPr 1-337 4-EtPhO cPrO 1-338 4-EtPhO cPr 1-3394-EtPhO CF₃O 1-340 4-EtPhO CF₃ 1-341 IndMeO iPrO 1-342 IndMeO cPrO 1-343IndMeO CF₃O 1-344 2-(2-cPen)EtO iPrO 1-345 2-(2-cPen)EtO cPrO 1-3462-(2-cPen)EtO CF₃O 1-347 2-PhPrO iPrO 1-348 2-PhPrO cPrO 1-349 2-PhPrOCF₃O 1-350 4-cPrBuO iPrO 1-351 4-cPrBuO cPrO 1-352 4-cPrBuO CF₃O 1-3532-(βNp)EtO iPrO 1-354 2-(βNp)EtO cPrO 1-355 2-(βNp)EtO CF₃O 1-3562-(3-CF₃Ph)EtO iPrO 1-357 2-(3-CF₃Ph)EtO cPrO 1-358 2-(3-CF₃Ph)EtO CF₃O1-359 2-(2-FPh)EtO iPrO 1-360 2-(2-FPh)EtO cPrO 1-361 2-(2-FPh)EtO CF₃O1-362 2-(4-CNPh)EtO iPrO 1-363 2-(4-CNPh)EtO cPrO 1-364 2-(4-CNPh)EtOCF₃O 1-365 2-(4-CF₃Ph)EtO iPrO 1-366 2-(4-CF₃Ph)EtO cPrO 1-3672-(4-CF₃Ph)EtO CF₃O 1-368 2-(4-MePh)EtO iPrO 1-369 2-(4-MePh)EtO cPrO1-370 2-(4-MePh)EtO CF₃O 1-371 2-(4-iPrOPh)EtO iPrO 1-3722-(4-iPrOPh)EtO cPr 1-373 2-(4-iPrOPh)EtO CF₃O 1-374 H iPrO 1-375 H cPrO1-376 H CF₃O 1-377 NO₂ iPrO 1-378 NO₂ cPrO 1-379 NO₂ CF₃O 1-380 CN iPrO1-381 CN cPrO 1-382 CN CF₃O 1-383 diMeN iPrO 1-384 diMeN cPrO 1-385diMeN CF₃O 1-386 F iPrO 1-387 F cPrO 1-388 F CF₃O 1-389 CF₃ iPrO 1-390CF₃ cPrO 1-391 CF₃ CF₃O 1-392 Bn iPrO 1-393 Bn cPrO 1-394 Bn CF₃O 1-395Ph iPrO 1-396 Ph cPrO 1-397 Ph CF₃O 1-398 iBu iPrO 1-399 iBu cPrO 1-400iBu CF₃O 1-401 Bu iPrO 1-402 Bu cPrO 1-403 Bu CF₃O 1-404 1-cPen iPrO1-405 1-cPen cPrO 1-406 1-cPen CF₃O 1-407 cHx iPrO 1-408 cHx cPrO 1-409cHx CF₃O 1-410 Bz iPrO 1-411 Bz cPrO 1-412 Bz CF₃O 1-413 iPrO iPrO 1-414iPrO cPrO 1-415 iPrO CF₃O 1-416 tBuO iPrO 1-417 tBuO cPrO 1-418 tBuOCF₃O 1-419 1-cPrEtO iPrO 1-420 1-cPrEtO cPrO 1-421 1-cPrEtO CF₃O 1-4221-cPnEtO iPrO 1-423 1-cPnEtO cPrO 1-424 1-cPnEtO CF₃O 1-425 1-PhEtO iPrO1-426 1-PhEtO cPrO 1-427 1-PhEtO CF₃O 1-428 THPO iPrO 1-429 THPO cPrO1-430 THPO CF₃O 1-431 cHxO iPrO 1-432 cHxO cPrO 1-433 cHxO CF₃O 1-434cHxO cPr 1-435 cPnO iPrO 1-436 cPnO cPrO 1-437 cPnO CF₃O 1-438 cPrMeOiPrO 1-439 cPrMeO cPrO 1-440 cPrMeO CF₃O 1-441 (1-Me-cPr)MeO iPrO 1-442(1-Me-cPr)MeO cPrO 1-443 (1-Me-cPr)MeO CF₃O 1-444 (1-Ph-cPr)MeO iPrO1-445 (1-Ph-cPr)MeO cPrO 1-446 (1-Ph-cPr)MeO CF₃O 1-447 cBuMeO iPrO1-448 cBuMeO cPrO 1-449 cBuMeO CF₃O 1-450 cPnMeO iPrO 1-451 cPnMeO cPrO1-452 cPnMeO CF₃O 1-453 cPnMeO cPr 1-454 cHxMeO iPrO 1-455 cHxMeO cPrO1-456 cHxMeO CF₃O 1-457 (1-Me-cHx)MeO iPrO 1-458 (1-Me-cHx)MeO cPrO1-459 (1-Me-cHx)MeO CF₃O 1-460 AdaMeO iPrO 1-461 AdaMeO cPrO 1-462AdaMeO CF₃O 1-463 cHpMeO iPrO 1-464 cHpMeO cPrO 1-465 cHpMeO CF₃O 1-4662-cPnEtO iPrO 1-467 2-cPnEtO cPrO 1-468 2-cPnEtO CHF₂O 1-469 2-cPnEtOCHF₂CH₂O 1-470 2-cPnEtO CF₃ 1-471 2-cPnEtO cPr 1-472 2-cPnEtO MeS 1-4732-(1-cPen)EtO iPrO 1-474 2-(1-cPen)EtO cPrO 1-475 2-(1-cPen)EtO CF₃O1-476 2-(1-cPen)EtO cPr 1-477 2-cHxEtO iPrO 1-478 2-cHxEtO cPrO 1-4792-cHxEtO CF₃O 1-480 3-cHxPrO iPrO 1-481 3-cHxPrO cPrO 1-482 3-cHxPrOCF₃O 1-483 CHF₂O iPrO 1-484 CHF₂O cPrO 1-485 CHF₂O CF₃O 1-486 CF₃O iPrO1-487 CF₃O cPrO 1-488 CF₃O CF₃O 1-489 CF₃CH₂O iPrO 1-490 CF₃CH₂O cPrO1-491 CF₃CH₂O CF₃O 1-492 CH₂FCH₂O iPrO 1-493 CH₂FCH₂O cPrO 1-494CH₂FCH₂O CF₃O 1-495 CHF₂CF₂O iPrO 1-496 CHF₂CF₂O cPrO 1-497 CHF₂CF₂OCF₃O 1-498 3-FPrO iPrO 1-499 3-FPrO cPrO 1-500 3-FPrO CF₃O 1-501CHF₂CF₂CH₂O iPrO 1-502 CHF₂CF₂CH₂O cPrO 1-503 CHF₂CF₂CH₂O CF₃O 1-5043-CF₃PrO iPrO 1-505 3-CF₃PrO cPrO 1-506 3-CF₃PrO CF₃O 1-507 3-CF₃CF₂PrOiPrO 1-508 3-CF₃CF₂PrO cPrO 1-509 3-CF₃CF₂PrO CF₃O 1-510 MeO iPrO 1-511MeO cPrO 1-512 MeO CF₃O 1-513 PhO iPrO 1-514 PhO cPrO 1-515 PhO CHF₂O1-516 PhO CF₃O 1-517 4-CF₃PhO iPrO 1-518 4-CF₃PhO cPrO 1-519 4-CF₃PhOCF₃O 1-520 BnO iPrO 1-521 BnO cPrO 1-522 BnO CF₃O 1-523 3-PhPreO iPrO1-524 3-PhPreO cPrO 1-525 3-PhPreO CF₃O 1-526 3-PhPryO iPrO 1-5273-PhPryO cPrO 1-528 3-PhPryO CF₃O 1-529 5-PhPnO iPrO 1-530 5-PhPnO cPrO1-531 5-PhPnO CF₃O 1-532 βNpMeO iPrO 1-533 βNpMeO cPrO 1-534 βNpMeO CF₃O1-535 αNpMeO iPrO 1-536 αNpMeO cPrO 1-537 αNpMeO CF₃O 1-538 PhthizMeOiPrO 1-539 PhthizMeO cPrO 1-540 PhthizMeO CF₃O 1-541 2-(αNp)EtO iPrO1-542 2-(αNp)EtO cPrO 1-543 2-(αNp)EtO CF₃O 1-544 2-(3,4-diMeOPh)EtOiPrO 1-545 2-(3,4-diMeOPh)EtO cPrO 1-546 2-(3,4-diMeOPh)EtO CF₃O 1-5472-(2-CF₃Ph)EtO iPrO 1-548 2-(2-CF₃Ph)EtO cPrO 1-549 2-(2-CF₃Ph)EtO CF₃O1-550 2-(2-Cl-4-FPh)EtO iPrO 1-551 2-(2-Cl-4-FPh)EtO cPrO 1-5522-(2-Cl-4-FPh)EtO CF₃O 1-553 2-(4-iPrOPh)EtO iPrO 1-554 2-(4-iPrOPh)EtOcPrO 1-555 2-(4-iPrOPh)EtO CF₃O 1-556 2-(4-tBuPh)EtO iPrO 1-5572-(4-tBuPh)EtO cPrO 1-558 2-(4-tBuPh)EtO CF₃O 1-559 3-(4-CF₃Ph)PrO iPrO1-560 3-(4-CF₃Ph)PrO cPrO 1-561 3-(4-CF₃Ph)PrO CF₃O 1-5623-(3,4-diMeOPh)PrO iPrO 1-563 3-(3,4-diMeOPh)PrO cPrO 1-5643-(3,4-diMeOPh)PrO CF₃O 1-565 3-(3-Py)PrO iPrO 1-566 3-(3-Py)PrO cPrO1-567 3-(3-Py)PrO CF₃O 1-568 3-(4-Py)PrO iPrO 1-569 3-(4-Py)PrO cPrO1-570 3-(4-Py)PrO CF₃O 1-571 2-PyrrEtO iPrO 1-572 2-PyrrEtO cPrO 1-5732-PyrrEtO CF₃O 1-574 3-PyrrPrO iPrO 1-575 3-PyrrPrO cPrO 1-576 3-PyrrPrOCF₃O 1-577 2-DOPyrdEtO iPrO 1-578 2-DOPyrdEtO cPrO 1-579 2-DOPyrdEtOCF₃O 1-580 2-PyrdEtO iPrO 1-581 2-PyrdEtO cPrO 1-582 2-PyrdEtO CF₃O1-583 2-(N-Ac-N-PhN)EtO iPrO 1-584 2-(N-Ac-N-PhN)EtO cPrO 1-5852-(N-Ac-N-PhN)EtO CF₃O 1-586 2-iBuOEtO iPrO 1-587 2-iBuOEtO cPrO 1-5882-iBuOEtO CF₃O 1-589 2-cPrMeOEtO iPrO 1-590 2-cPrMeOEtO cPrO 1-5912-cPrMeOEtO CF₃O 1-592 2-cPrMeOEtO cPr 1-593 2-iPrOEtO iPrO 1-5942-iPrOEtO cPrO 1-595 2-iPrOEtO CF₃O 1-596 2-cPnOEtO iPrO 1-597 2-cPnOEtOcPrO 1-598 2-cPnOEtO CF₃O 1-599 2-cPnOEtO cPr 1-600 2-(4-FPhO)EtO iPrO1-601 2-(4-FPhO)EtO cPrO 1-602 2-(4-FPhO)EtO CF₃O 1-603 2-BnOEtO iPrO1-604 2-BnOEtO cPrO 1-605 2-BnOEtO CF₃O 1-606 2-DHBDMeO iPrO 1-6072-DHBDMeO cPrO 1-608 2-DHBDMeO CF₃O 1-609 4,4-diMeBunO iPrO 1-6104,4-diMeBunO cPrO 1-611 4,4-diMeBunO CF₃O 1-612 iBuS iPrO 1-613 iBuScPrO 1-614 iBuS CF₃O 1-615 2-(4-iBuOPh)EtO iPrO 1-616 2-(4-iBuOPh)EtOcPrO 1-617 2-(4-iBuOPh)EtO CF₃O 1-618 2-(4-iBuOPh)EtO cPr 1-6192-(3,4-diMeOPh)EtO iPrO 1-620 2-(3,4-diMeOPh)EtO cPrO 1-6212-(3,4-diMeOPh)EtO CHF₂O 1-622 2-(3,4-diMeOPh)EtO CF₃O 1-6232-(3,4-diMeOPh)EtO CHF₂CH₂O 1-624 2-(3,4-diMeOPh)EtO cPr 1-6252-(3,4-diMeOPh)EtO MeS 1-626 2-(3,4-diMeOPh)EtO CF₃ 1-6272-(3,4-diMeOPh)EtO Cl 1-628 2-(4-PyrdPh)EtO iPrO 1-629 2-(4-PyrdPh)EtOcPrO 1-630 2-(4-PyrdPh)EtO CF₃O 1-631 2-(4-PyrdPh)EtO cPr 1-6322-(4-PyrdPh)EtO Cl

In the above Table 1, preferred examples of the compound having Formula(I-1) according to the present invention are those denoted by ExemplaryCompound Nos. 1-58 to 1-110, 1-128 to 1-144, 1-162 to 1-178, 1-196 to1-212, 1-274 to 1-282, 1-438 to 1-443, 1-504 to 1-506, and 1-517 to1-519; and more preferred examples are

-   Exemplary Compound No. 1-58: (Example 15)    4-(2-cyclopropylethoxy)-N-((Z)-2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   Exemplary Compound No. 1-60: (Example 16)    4-(2-cyclopropylethoxy)-N-((Z)-2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   Exemplary Compound No. 1-61: (Example 10)    4-(2-cyclopropylethoxy)-N-((Z)-2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   Exemplary Compound No. 1-62: (Example 11)    4-(2-cyclopropylethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   Exemplary Compound No. 1-64: (Example 12)    4-(2-cyclopropylethoxy)-N-((Z)-2-[4-(2,2-difluoroethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   Exemplary Compound No. 1-68: (Example 9)    4-(2-cyclopropylethoxy)-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   Exemplary Compound No. 1-69: (Example 19)    4-(2-cyclopropylethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide,-   Exemplary Compound No. 1-72: (Example 18)    4-(2-cyclopropylethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(1H-pyrrol-1-yl)phenyl]vinyl}benzamide,-   Exemplary Compound No. 1-109: (Example 14)    N-((Z)-2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-cyclopropylethoxy)benzamide,-   Exemplary Compound No. 1-129: (Example 7)    N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   Exemplary Compound No. 1-130: (Example 6)    N-((Z)-2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   Exemplary Compound No. 1-132: (Example 3)    N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl)}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   Exemplary Compound No. 1-138: (Example 5)    N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   Exemplary Compound No. 1-141: (Example 8)    N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(methylthio)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   Exemplary Compound No. 1-144: (Example 1)    N-((Z)-2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide,-   Exemplary Compound No. 1-163: (Example 27)    4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide,-   Exemplary Compound No. 1-166: (Example 23)    4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   Exemplary Compound No. 1-172: (Example 25)    N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide,-   Exemplary Compound No. 1-196: (Example 83)    4-[2-(4-chlorophenyl)ethoxy]-N-((Z)-2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   Exemplary Compound No. 1-198: (Example 81)    4-[2-(4-chlorophenyl)ethoxy]-N-((Z)-2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   Exemplary Compound No. 1-199: (Example 78)    4-[2-(4-chlorophenyl)ethoxy]-N-((Z)-2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   Exemplary Compound No. 1-200: (Example 79)    4-[2-(4-chlorophenyl)ethoxy]-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   Exemplary Compound No. 1-206: (Example 80)    4-[2-(4-chlorophenyl)ethoxy]-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   Exemplary Compound No. 1-212: (Example 82)    4-[2-(4-chlorophenyl)ethoxy]-N-((Z)-2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide,-   Exemplary Compound No. 1-277: (Example 108)    N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide,-   Exemplary Compound No. 1-440: (Example 104)    4-(cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,-   Exemplary Compound No. 1-506: (Example 107)    N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(4,4,4-trifluorobutoxy)benzamide,    and-   Exemplary Compound No. 1-519: (Example 112)    N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide.

TABLE 2 Exemplary compound table 2 (I-2)

Compound No. R^(c) R^(d) 2-1 βNp 4-iPrOPh 2-2 3-MeO-4-cPnOPh 4-iPrOPh2-3 3,4-MEDOPh 4-iPrOPh 2-4 2-i-BuOPh 4-iPrOPh 2-5 3-i-BuOPh 4-iPrOPh2-6 4-i-BuOPh βNp 2-7 4-i-BuOPh 6-MeO(βNp) 2-8 4-i-BuOPh Chr 2-94-i-BuOPh 6-DHBD 2-10 4-i-BuOPh 2-iPrOPh 2-11 4-i-BuOPh 3-iPrOPh 2-124-i-BuOPh 3,5-diBnOPh 2-13 4-i-BuOPh 3,5-diMeOPh 2-14 4-i-BuOPh3,4,5-triMeOPh 2-15 4-i-BuOPh 6-MeO(3-Py) 2-16 4-i-BuOPh 6-CF₃(3-Py)2-17 4-i-BuOPh Quin 2-18 4-i-BuOPh 1-iBuPip 2-19 4-i-BuO(3-Py) 4-iPrOPh2-20 4-i-BuO(3-F)Ph 4-iPrOPh 2-21 4-i-BuO(2-F)Ph 4-iPrOPh

In the above Table 2, preferred examples of the compound having Formula(I-2) according to the present invention are

-   Exemplary Compound No. 2-6:    N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(2-naphthyl)vinyl]-4-isobutoxybenzamide,-   Exemplary Compound No. 2-16:    N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[6-(trifluoromethyl)pyridin-3-yl]vinyl}-4-isobutoxybenzamide,-   Exemplary Compound No. 2-19:    N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-6-isobutoxynicotinamide,    and-   Exemplary Compound No. 2-21:    2-fluoro-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-isobutoxybenzamide.

TABLE 3 Exemplary compound table 3 (I-3)

Compound No. R^(e) R^(f) R^(g) R^(h) 3-1 Me Me iPrO 2-HOPrNH 3-2 Me MeiPrO 2-HOBuNH 3-3 Me Me iPrO (1-HO-cPr)MeNH 3-4 Me Me iPrO 2-HO-2-MePrNH3-5 Me Me iPrO 2,3-diHOPrNH 3-6 Me Me iPrO 1-HO-2-MeEtNH 3-7 Me Me iPrO2-HO-1,1-diMeEtNH 3-8 Me Me iPrO 2-HOEt(Me)N 3-9 Me Me iPrO 2-AcOEtNH3-10 Me Me iPrO 3-HOPrNH 3-11 Me Me iPrO 4-HOBuNH 3-12 Me Me iPrO2-MeOEtNH 3-13 Me Me iPrO THFMeNH 3-14 Me Me iPrO MeOCOMeNH 3-15 Me MeiPrO HOOCMeNH 3-16 Me Me iPrO PhNHCOOEtNH 3-17 Me Me iPrO 2-HOPhNH 3-18Me Me iPrO 3-HOPhNH 3-19 Me Me iPrO PhNH 3-20 Me Me iPrO FurMeNH 3-21 MeMe iPrO 2-PyMeNH 3-22 Me Me iPrO 4-HOPhNH 3-23 Me Me iPrO ThiMeNH 3-24Me Me iPrO 2-PhEtNH 3-25 Me Me iPrO 2-(2-Py)EtNH 3-26 Me Me iPrOH₂NCOMeNH 3-27 Me Me iPrO 2-HO-cPnNH 3-28 Me Me iPrO CNMeNH 3-29 Me MeiPrO PrNH 3-30 Me Me iPrO 2-FEtNH 3-31 Me Me iPrO H₂N 3-32 Me Me iPrOH₂NEtNH 3-33 Me Me iPrO AcNHEtNH 3-34 Me Me iPrO H₂NCONHEtNH 3-35 Me MeiPrO BocNHEtNH 3-36 Me Me iPrO PhtlNEtNH 3-37 Me Me iPrO 2-DDQZEtNH 3-38Me Me iPrO Pyrd 3-39 Me Me iPrO Mor 3-40 Me Me iPrO 4-BocPiz 3-41 Me MeiPrO HO 3-42 Me Me iPrO EtO 3-43 Me Me iPrO 2-HOEtO 3-44 Me Me iPrOEtONH 3-45 Me Me iPrO 2-HOEtONH 3-46 Me Me iPrO 2-(MorAcO)EtNH 3-47 MeMe iPrO 2-(2-(HOOC)EtCOO)EtNH 3-48 Me Me cPrO 2-HOPrNH 3-49 Me Me cPrO2-HOBuNH 3-50 Me Me cPrO (1-HO-cPr)MeNH 3-51 Me Me cPrO 1-HO-2-MeEtNH3-52 Me Me cPrO 2-AcOEtNH 3-53 Me Me cPrO 2-HOPhNH 3-54 Me Me cPrO PrNH3-55 Me Me cPrO H₂NCOMeNH 3-56 Me Me cPrO 2-(MorAcO)EtNH 3-57 Me Me cPrO2-(2-(HOOC)EtCOO)EtNH 3-58 Me Me CF₃O 2-HOPrNH 3-59 Me Me CF₃O 2-HOBuNH3-60 Me Me CF₃O (1-HO-cPr)MeNH 3-61 Me Me CF₃O 1-HO-2-MeEtNH 3-62 Me MeCF₃O 2-AcOEtNH 3-63 Me Me CF₃O 2-HOPhNH 3-64 Me Me CF₃O PrNH 3-65 Me MeCF₃O H₂NCOMeNH 3-66 Me Me CF₃O 2-(MorAcO)EtNH 3-67 Me Me CF₃O2-(2-(HOOC)EtCOO)EtNH 3-68 Me Me cPr 2-HOPrNH 3-69 Me Me cPr 2-HOBuNH3-70 Me Me cPr (1-HO-cPr)MeNH 3-71 Me Me cPr 1-HO-2-MeEtNH 3-72 Me MecPr 2-AcOEtNH 3-73 Me Me cPr 2-HOPhNH 3-74 Me Me cPr PrNH 3-75 Me Me cPrH₂NCOMeNH 3-76 Me Me cPr 2-(MorAcO)EtNH 3-77 Me Me cPr2-(2-(HOOC)EtCOO)EtNH 3-78 H cPr iPrO 2-HOPrNH 3-79 H cPr iPrO 2-HOBuNH3-80 H cPr iPrO (1-HO-cPr)MeNH 3-81 H cPr iPrO 1-HO-2-MeEtNH 3-82 H cPriPrO 2-AcOEtNH 3-83 H cPr iPrO 2-HOPhNH 3-84 H cPr iPrO PrNH 3-85 H cPriPrO H₂NCOMeNH 3-86 H cPr iPrO 2-(MorAcO)EtNH 3-87 H cPr iPrO2-(2-(HOOC)EtCOO)EtNH 3-88 H cPr cPrO 2-HOPrNH 3-89 H cPr cPrO 2-HOBuNH3-90 H cPr cPrO (1-HO-cPr)MeNH 3-91 H cPr cPrO 1-HO-2-MeEtNH 3-92 H cPrcPrO 2-AcOEtNH 3-93 H cPr cPrO 2-HOPhNH 3-94 H cPr cPrO PrNH 3-95 H cPrcPrO H₂NCOMeNH 3-96 H cPr cPrO 2-(MorAcO)EtNH 3-97 H cPr cPrO2-(2-(HOOC)EtCOO)EtNH 3-98 H cPr CF₃O 2-HOPrNH 3-99 H cPr CF₃O 2-HOBuNH3-100 H cPr CF₃O (1-HO-cPr)MeNH 3-101 H cPr CF₃O 1-HO-2-MeEtNH 3-102 HcPr CF₃O 2-AcOEtNH 3-103 H cPr CF₃O 2-HOPhNH 3-104 H cPr CF₃O PrNH 3-105H cPr CF₃O H₂NCOMeNH 3-106 H cPr CF₃O 2-(MorAcO)EtNH 3-107 H cPr CF₃O2-(2-(HOOC)EtCOO)EtNH 3-108 H cPr cPr 2-HOPrNH 3-109 H cPr cPr 2-HOBuNH3-110 H cPr cPr (1-HO-cPr)MeNH 3-111 H cPr cPr 1-HO-2-MeEtNH 3-112 H cPrcPr 2-AcOEtNH 3-113 H cPr cPr 2-HOPhNH 3-114 H cPr cPr PrNH 3-115 H cPrcPr H₂NCOMeNH 3-116 H cPr cPr 2-(MorAcO)EtNH 3-117 H cPr cPr2-(HOOC)EtCOO)EtNH 3-118 H Ph iPrO 2-HOPrNH 3-119 H Ph iPrO 2-HOBuNH3-120 H Ph iPrO (1-HO-cPr)MeNH 3-121 H Ph iPrO 1-HO-2-MeEtNH 3-122 H PhiPrO 2-AcOEtNH 3-123 H Ph iPrO 2-HOPhNH 3-124 H Ph iPrO PrNH 3-125 H PhiPrO H₂NCOMeNH 3-126 H Ph iPrO 2-(MorAcO)EtNH 3-127 H Ph iPrO2-(2-(HOOC)EtCOO)EtNH 3-128 H Ph cPrO 2-HOPrNH 3-129 H Ph cPrO 2-HOBuNH3-130 H Ph cPrO (1-HO-cPr)MeNH 3-131 H Ph cPrO 1-HO-2-MeEtNH 3-132 H PhcPrO 2-AcOEtNH 3-133 H Ph cPrO 2-HOPhNH 3-134 H Ph cPrO PrNH 3-135 H PhcPrO H₂NCOMeNH 3-136 H Ph cPrO 2-(MorAcO)EtNH 3-137 H Ph cPrO2-(2-(HOOC)EtCOO)EtNH 3-138 H Ph CF₃O 2-HOPrNH 3-139 H Ph CF₃O 2-HOBuNH3-140 H Ph CF₃O (1-HO-cPr)MeNH 3-141 H Ph CF₃O 1-HO-2-MeEtNH 3-142 H PhCF₃O 2-AcOEtNH 3-143 H Ph CF₃O 2-HOPhNH 3-144 H Ph CF₃O PrNH 3-145 H PhCF₃O H₂NCOMeNH 3-146 H Ph CF₃O 2-(MorAcO)EtNH 3-147 H Ph CF₃O2-(2-(HOOC)EtCOO)EtNH 3-148 H Ph cPr 2-HOPrNH 3-149 H Ph cPr 2-HOBuNH3-150 H Ph cPr (1-HO-cPr)MeNH 3-151 H Ph cPr 1-HO-2-MeEtNH 3-152 H PhcPr 2-AcOEtNH 3-153 H Ph cPr 2-HOPhNH 3-154 H Ph cPr PrNH 3-155 H Ph cPrH₂NCOMeNH 3-156 H Ph cPr 2-(MorAcO)EtNH 3-157 H Ph cPr2-(2-(HOOC)EtCOO)EtNH 3-158 H 4-MeOPh iPrO 2-HOPrNH 3-159 H 4-MeOPh iPrO2-HOBuNH 3-160 H 4-MeOPh iPrO (1-HO-cPr)MeNH 3-161 H 4-MeOPh iPrO1-HO-2-MeEtNH 3-162 H 4-MeOPh iPrO 2-AcOEtNH 3-163 H 4-MeOPh iPrO2-HOPhNH 3-164 H 4-MeOPh iPrO PrNH 3-165 H 4-MeOPh iPrO H₂NCOMeNH 3-166H 4-MeOPh iPrO 2-(MorAcO)EtNH 3-167 H 4-MeOPh iPrO 2-(2-(HOOC)EtCOO)EtNH3-168 H 4-MeOPh cPrO 2-HOPrNH 3-169 H 4-MeOPh cPrO 2-HOBuNH 3-170 H4-MeOPh cPrO (1-HO-cPr)MeNH 3-171 H 4-MeOPh cPrO 1-HO-2-MeEtNH 3-172 H4-MeOPh cPrO 2-AcOEtNH 3-173 H 4-MeOPh cPrO 2-HOPhNH 3-174 H 4-MeOPhcPrO PrNH 3-175 H 4-MeOPh cPrO H₂NCOMeNH 3-176 H 4-MeOPh cPrO2-(MorAcO)EtNH 3-177 H 4-MeOPh cPrO 2-(2-(HOOC)EtCOO)EtNH 3-178 H4-MeOPh CF₃O 2-HOPrNH 3-179 H 4-MeOPh CF₃O 2-HOBuNH 3-180 H 4-MeOPh CF₃O(1-HO-cPr)MeNH 3-181 H 4-MeOPh CF₃O 1-HO-2-MeEtNH 3-182 H 4-MeOPh CF₃O2-AcOEtNH 3-183 H 4-MeOPh CF₃O 2-HOPhNH 3-184 H 4-MeOPh CF₃O PrNH 3-185H 4-MeOPh CF₃O H₂NCOMeNH 3-186 H 4-MeOPh CF₃O 2-(MorAcO)EtNH 3-187 H4-MeOPh CF₃O 2-(2-(HOOC)EtCOO)EtNH 3-188 H 4-MeOPh cPr 2-HOPrNH 3-189 H4-MeOPh cPr 2-HOBuNH 3-190 H 4-MeOPh cPr (1-HO-cPr)MeNH 3-191 H 4-MeOPhcPr 1-HO-2-MeEtNH 3-192 H 4-MeOPh cPr 2-AcOEtNH 3-193 H 4-MeOPh cPr2-HOPhNH 3-194 H 4-MeOPh cPr PrNH 3-195 H 4-MeOPh cPr H₂NCOMeNH 3-196 H4-MeOPh cPr 2-(MorAcO)EtNH 3-197 H 4-MeOPh cPr 2-(2-(HOOC)EtCOO)EtNH3-198 H 4-diMeNPh iPrO 2-HOPrNH 3-199 H 4-diMeNPh iPrO 2-HOBuNH 3-200 H4-diMeNPh iPrO (1-HO-cPr)MeNH 3-201 H 4-diMeNPh iPrO 1-HO-2-MeEtNH 3-202H 4-diMeNPh iPrO 2-AcOEtNH 3-203 H 4-diMeNPh iPrO 2-HOPhNH 3-204 H4-diMeNPh iPrO PrNH 3-205 H 4-diMeNPh iPrO H₂NCOMeNH 3-206 H 4-diMeNPhiPrO 2-(MorAcO)EtNH 3-207 H 4-diMeNPh iPrO 2-(2-(HOOC)EtCOO)EtNH 3-208 H4-diMeNPh cPrO 2-HOPrNH 3-209 H 4-diMeNPh cPrO 2-HOBuNH 3-210 H4-diMeNPh cPrO (1-HO-cPr)MeNH 3-211 H 4-diMeNPh cPrO 1-HO-2-MeEtNH 3-212H 4-diMeNPh cPrO 2-AcOEtNH 3-213 H 4-diMeNPh cPrO 2-HOPhNH 3-214 H4-diMeNPh cPrO PrNH 3-215 H 4-diMeNPh cPrO H₂NCOMeNH 3-216 H 4-diMeNPhcPrO 2-(MorAcO)EtNH 3-217 H 4-diMeNPh cPrO 2-(2-(HOOC)EtCOO)EtNH 3-218 H4-diMeNPh CF₃O 2-HOPrNH 3-219 H 4-diMeNPh CF₃O 2-HOBuNH 3-220 H4-diMeNPh CF₃O (1-HO-cPr)MeNH 3-221 H 4-diMeNPh CF₃O 1-HO-2-MeEtNH 3-222H 4-diMeNPh CF₃O 2-AcOEtNH 3-223 H 4-diMeNPh CF₃O 2-HOPhNH 3-224 H4-diMeNPh CF₃O PrNH 3-225 H 4-diMeNPh CF₃O H₂NCOMeNH 3-226 H 4-diMeNPhCF₃O 2-(MorAcO)EtNH 3-227 H 4-diMeNPh CF₃O 2-(2-(HOOC)EtCOO)EtNH 3-228 H4-diMeNPh cPr 2-HOPrNH 3-229 H 4-diMeNPh cPr 2-HOBuNH 3-230 H 4-diMeNPhcPr (1-HO-cPr)MeNH 3-231 H 4-diMeNPh cPr 1-HO-2-MeEtNH 3-232 H 4-diMeNPhcPr 2-AcOEtNH 3-233 H 4-diMeNPh cPr 2-HOPhNH 3-234 H 4-diMeNPh cPr PrNH3-235 H 4-diMeNPh cPr H₂NCOMeNH 3-236 H 4-diMeNPh cPr 2-(MorAcO)EtNH3-237 H 4-diMeNPh cPr 2-(2-(HOOC)EtCOO)EtNH 3-238 H 4-ClPh iPrO 2-HOPrNH3-239 H 4-ClPh iPrO 2-HOBuNH 3-240 H 4-ClPh iPrO (1-HO-cPr)MeNH 3-241 H4-ClPh iPrO 1-HO-2-MeEtNH 3-242 H 4-ClPh iPrO 2-AcOEtNH 3-243 H 4-ClPhiPrO 2-HOPhNH 3-244 H 4-ClPh iPrO PrNH 3-245 H 4-ClPh iPrO H₂NCOMeNH3-246 H 4-ClPh iPrO 2-(MorAcO)EtNH 3-247 H 4-ClPh iPrO2-(2-(HOOC)EtCOO)EtNH 3-248 H 4-ClPh cPrO 2-HOPrNH 3-249 H 4-ClPh cPrO2-HOBuNH 3-250 H 4-ClPh cPrO (1-HO-cPr)MeNH 3-251 H 4-ClPh cPrO1-HO-2-MeEtNH 3-252 H 4-ClPh cPrO 2-AcOEtNH 3-253 H 4-ClPh cPrO 2-HOPhNH3-254 H 4-ClPh cPrO PrNH 3-255 H 4-ClPh cPrO H₂NCOMeNH 3-256 H 4-ClPhcPrO 2-(MorAcO)EtNH 3-257 H 4-ClPh cPrO 2-(2-(HOOC)EtCOO)EtNH 3-258 H4-ClPh CF₃O 2-HOPrNH 3-259 H 4-ClPh CF₃O 2-HOBuNH 3-260 H 4-ClPh CF₃O(1-HO-cPr)MeNH 3-261 H 4-ClPh CF₃O 1-HO-2-MeEtNH 3-262 H 4-ClPh CF₃O2-AcOEtNH 3-263 H 4-ClPh CF₃O 2-HOPhNH 3-264 H 4-ClPh CF₃O PrNH 3-265 H4-ClPh CF₃O H₂NCOMeNH 3-266 H 4-ClPh CF₃O 2-(MorAcO)EtNH 3-267 H 4-ClPhCF₃O 2-(2-(HOOC)EtCOO)EtNH 3-268 H 4-ClPh cPr 2-HOPrNH 3-269 H 4-ClPhcPr 2-HOBuNH 3-270 H 4-ClPh cPr (1-HO-cPr)MeNH 3-271 H 4-ClPh cPr1-HO-2-MeEtNH 3-272 H 4-ClPh cPr 2-AeOEtNH 3-273 H 4-ClPh cPr 2-HOPhNH3-274 H 4-ClPh cPr PrNH 3-275 H 4-ClPh cPr H₂NCOMeNH 3-276 H 4-ClPh cPr2-(MorAcO)EtNH 3-277 H 4-ClPh cPr 2-(2-(HOOC)EtCOO)EtNH

In the above Table 3, preferred examples of the compound having Formula(I-3) according to the present invention are those denoted by ExemplaryCompound Nos. 3-48 to 3-77, 3-88 to 3-117, 3-128 to 3-157, 3-168 to3-197, 3-208 to 3-237, and 3-248 to 3-277; and more preferable examplesare

-   Exemplary Compound No. 3-92:    2-({(2Z)-2-{[4-(2-cyclopropylethoxy)benzoyl]amino}-3-[4-(cyclopropyloxy)phenyl]propen-2-oyl}amino)ethyl    acetate,-   Exemplary Compound No. 3-102:    2-{[(2Z)-2-{[4-(2-cyclopropylethoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propen-2-oyl]amino}ethyl    acetate,-   Exemplary Compound No. 3-112: (Example 20)    2-{[(2Z)-2-{[4-(2-cyclopropylethoxy)benzoyl]amino}-3-(4-cyclopropylphenyl)propen-2-oyl]amino}ethyl    acetate,-   Exemplary Compound No. 3-172:    2-{[(2Z)-3-[4-(cyclopropyloxy)phenyl]-2-({4-[2-(4-methoxyphenyl)ethoxy]benzoyl}amino)propen-2-oyl]amino}ethyl    acetate,-   Exemplary Compound No. 3-182:    2-({(2Z)-2-({4-[2-(4-methoxyphenyl)ethoxy]benzoyl}amino)-3-[4-(trifluoromethoxy)phenyl]propen-2-oyl}amino)ethyl    acetate,-   Exemplary Compound No. 3-192:    2-{[(2Z)-3-(4-cyclopropylphenyl)-2-({4-[2-(4-methoxyphenyl)ethoxy]benzoyl}amino)propen-2-oyl]amino}ethyl    acetate,-   Exemplary Compound No. 3-212:    2-({(2Z)-3-[4-(cyclopropyloxy)phenyl]-2-[(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)amino]propen-2-oyl}amino)ethyl    acetate,-   Exemplary Compound No. 3-222:    2-({(2Z)-2-[(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)amino]-3-[4-(trifluoromethoxy)phenyl]propen-2-oyl}amino)ethyl    acetate,-   Exemplary Compound No. 3-232:    2-({(2Z)-3-(4-cyclopropylphenyl)-2-[(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)amino]propen-2-oyl}amino)ethyl    acetate,-   Exemplary Compound No. 3-252:    2-({(2Z)-2-({4-[2-(4-chlorophenyl)ethoxy]benzoyl}amino)-3-[4-(cyclopropoxy)phenyl]propen-2-oyl}amino)ethyl    acetate,-   Exemplary Compound No. 3-262:    2-({(2Z)-2-({4-[2-(4-chlorophenyl)ethoxy]benzoyl}amino)-3-[4-(trifluoromethoxy)phenyl]propen-2-oyl}amino)ethyl    acetate, and-   Exemplary Compound No. 3-272:    2-{[(2Z)-2-({4-[2-(4-chlorophenyl)ethoxy]benzoyl}amino)-3-(4-cyclopropylphenyl)propen-2-oyl]amino}ethyl    acetate.    (General Manufacturing Process)

The compound having Formula (I) according to the present invention canbe manufactured according to the following processes.

The following manufacturing processes are generally conducted accordingto known methods described in, for example, “ORGANIC FUNCTIONAL GROUPPREPARATIONS”, 2nd edition, ACADEMIC PRESS, INC., (1989) or“Comprehensive Organic Transformations”, VCH Publishers Inc., (1989).

Some functional groups, in the stage of raw materials to intermediatesfor manufacturing, require to be protected by suitable protecting groupswhich can be readily converted to the functional groups. In such a case,desired compounds can be obtained by removing the protecting groupsaccording to need.

Examples of such functional groups include a hydroxyl group, a carboxylgroup, a carbonyl group, and an amino group. Protecting groups for thesefunctional groups are described in, for example, Greene and Wuts,“Protective Groups in Organic Synthesis”, 3rd edition, John Wiley &Sons, Inc., (1999) and can be optionally used according to reactionconditions.

Carboxyl protecting groups, for example, C₁-C₆ alkyl (for example,methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl), C₇-C₁₁ aralkyl(for example, benzyl), phenyl, trityl, silyl (for example,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, and tert-butyldiethylsilyl), and C₂-C₆ alkenyl(for example, 1-allyl) are used. These groups may be substituted with,for example, one to three halogen atoms (for example, fluorine,chlorine, bromine, and iodine), C₁-C₆ alkoxy (for example, methoxy,ethoxy, and propoxy), or nitro.

Hydroxyl protecting groups, for example, C₁-C₆ alkyl (for example,methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl), phenyl,trityl, C₇-C₁₁ aralkyl (for example, benzyl), formyl, C₁-C₆alkylcarbonyl (for example, acetyl and propionyl), benzoyl, C₇-C₁₁aralkylcarbonyl (for example, benzylcarbonyl), 2-tetrahydropyranyl,2-tetrahydrofuranyl, silyl (for example, trimethylsilyl, triethylsilyl,dimethylphenylsilyl, tert-butyldimethylsilyl, andtert-butyldiethylsilyl), and C₂-C₆ alkenyl (for example, 1-allyl) areused. These groups may be substituted with, for example, one to threehalogen atoms (for example, fluorine, chlorine, bromine, and iodine),C₁-C₆ alkyl (for example, methyl, ethyl, and n-propyl), C₁-C₆ alkoxy(for example, methoxy, ethoxy, and propoxy), or nitro.

Carbonyl protecting groups, for example, cyclic acetal (for example,1,3-dioxane) and noncyclic acetal (for example, di-C₁-C₆ alkylacetal)are used.

Amino protecting groups, for example, formyl, C₁-C₆ alkylcarbonyl (forexample, acetyl and propionyl), C₁-C₆ alkoxycarbonyl (for example,methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl), benzoyl,C₇-C₁₁ aralkylcarbonyl (for example, benzylcarbonyl), C₇-C₁₄aralkyloxycarbonyl (for example, benzyloxycarbonyl and9-fluorenylmethoxycarbonyl), trityl, phthaloyl,N,N-dimethylaminomethylene, silyl (for example, trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, andtert-butyldiethylsilyl), and C₂-C₆ alkenyl (for example, 1-allyl) areused. These groups may be substituted with, for example, one to threehalogen atoms (for example, fluorine, chlorine, bromine, and iodine),C₁-C₆ alkoxy (for example, methoxy, ethoxy, and propoxy), or nitro.

The above-mentioned protecting groups are removed by known methods, suchas, a method using acid, base, ultraviolet light, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate, or a trialkylsilyl halide (for example,trimethylsilyl iodide or trimethylsilyl bromide), or a reducing method.

The following process A is for manufacturing a compound having Formula(I).

In the above formula, R¹, R², and X represent the same meanings as thosedescribed above.

Process A1 is a process for manufacturing a compound having Formula (I)and is conducted by a reaction between a compound having formula (II)and a compound having formula (III) in the presence of a solvent.

The compound having formula (III) used in the above reaction ispreferably a primary or secondary aliphatic amine such as methylamine,ethylamine, propylamine, isopropylamine, butylamine, isobutylamine,2-fluoroethylamine, 2-methoxyethylamine, ethanolamine, ethoxyamine,aminoacetonitrile, 1-amino-2-propanol, 2-amino-2-methyl-1-propanol,2-amino-1-propanol, 3-amino-1-propanol, N-acetylethylenediamine,benzylamine, furfurylamine, thiophene-2-methylamine,2-(aminomethyl)pyridine, 1-phenylethylamine, 2-phenylethylamine,dimethylamine, diethylamine, pyrrolidine, piperidine, morpholine,piperazine, or 2-(methylamino)ethanol; or an aromatic amine such asaniline, 2-aminophenol, 3-aminophenol, 4-aminophenol, 4-fluoroaniline,4-chloroaniline, or 4-methoxyaniline; more preferably a primaryaliphatic amine; and particularly preferably ethanolamine.

Examples of the solvent used in the above reaction include aliphatichydrocarbons such as hexane, heptane, ligroin, and petroleum ether;aromatic hydrocarbons such as toluene, benzene, and xylene; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane, and diethylene glycol dimethyl ether; amides such asN,N-dimethylacetamide and hexamethylphosphoric acid triamide; and loweralkyl alcohols such as methanol, ethanol, propanol, and butanol. Inorder to obtain a (Z)-isomer as a position isomer, alcohols and ethersare preferred, alcohols are more preferred, and ethanol is particularlymore preferred. In order to obtain an (E)-isomer as a position isomer,aromatic hydrocarbons are preferred, and toluene is more preferred.

The reaction temperature varies depending on, for example, the rawcompounds, the solvent, and the kind of the base and is usually 0° C. to200° C. and preferably 25° C. to 80° C.

The reaction time varies depending on, for example, the raw materials,the solvent, the base, and the reaction temperature and is usually 1minute to 24 hours and preferably 10 minutes to 6 hours.

After the completion of the reaction, the target compound in thisprocess is collected from the reaction mixture according to aconventional method. For example, the reaction mixture is optionallyneutralized or filtered for removal of insoluble substances, if present.The reaction solution is extracted with an organic solvent which is notmiscible with water, such as toluene, and is washed with water. Theorganic layer containing the target compound is concentrated underreduced pressure to remove the solvent to give the target compound.

The obtained target compound can be separated and purified, according toneed, by a usual method such as recrystallization, reprecipitation, or amethod which is widely used for separation and purification of organiccompounds (for example, adsorption column chromatography using a carriersuch as silica gel, alumina, or Florisil composed of magnesium-silicagel; partition column chromatography using a carrier such as SephadexLH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), or Diaion HP-20(Mitsubishi Chemical Company); ion-exchange chromatography; ornormal-phase and reversed-phase column chromatography using silica gelor alkylated silica gel, and preferably silica-gel columnchromatography).

The isomers can be separated, if necessary, by any of theabove-mentioned separation/purification means at a suitable stage afterthe completion of the reaction of the above each process or after thecompletion of a desired process.

When a compound having a structure of Formula (I) is present as isomers,such as regioisomers, rotational isomers, or diastereomers, the isomerscan be separated, if desired, into their respective isometric forms bythe above-mentioned separation/purification means. In this process,(E)-isomer and (Z)-isomer are produced as regioisomers and can beseparated from each other by the above-mentioned separation/purificationmeans.

When a compound having a structure of Formula (I) exists as a racemicmixture, the mixture can be separated into (S)-isomer and (R)-isomer bya conventional optical resolution method.

The following Process B is for manufacturing a compound having Formula(II).

In the above formula, R¹ and R² represent the same meanings as thosedescribed above.

Process B1 is a process for manufacturing a compound having Formula (II)and is conducted by a reaction between a compound having a formula (IV)and a compound having a formula (V) in the presence or absence of asolvent.

Examples of the solvent used in the above reaction include aliphatichydrocarbons such as hexane, heptane, ligroin, and petroleum ether;aromatic hydrocarbons such as toluene, benzene, and xylene; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane, and diethylene glycol dimethyl ether; amides such asN,N-dimethylacetamide and hexamethylphosphoric acid triamide; and acidanhydrides such as acetic anhydride. In particular, acid anhydrides arepreferred, and acetic anhydride is more preferred.

The reaction temperature varies depending on, for example, the rawmaterials, the solvent, and the kind of the base and is usually 25° C.to 200° C. and preferably 80° C. to 120° C.

The reaction time varies depending on, for example, the raw materials,the solvent, the base, and the reaction temperature and is usually 1minute to 1 hour and preferably 10 minutes to 6 hours.

The compound having formula (II) prepared in this process is obtained asa mixture of regioisomers, (E)-isomer and (Z)-isomer, in which the(Z)-isomer is preferred in general. In order to manufacture the(E)-isomer, the ratio of the (E)-isomer can be increased by furthertreating the compound having formula (II) prepared in this process withan acid.

Examples of the acid used in the above acid treatment include Bronstedacids, for example, inorganic acids, such as hydrochloric acid,hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid,and organic acids, such as acetic acid, formic acid, oxalic acid,methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid,trifluoroacetic acid, and trifluoromethanesulfonic acid; Lewis acidssuch as zinc chloride, tin tetrachloride, boron trichloride, borontrifluoride, and boron tribromide; and acidic ion-exchange resins.Inorganic acids are preferred, and hydrobromic acid is more preferred.

The solvent used in the above acid treatment is preferably acetic acid.

The reaction temperature varies depending on, for example, the rawmaterials and the kinds of the acid and solvent used and is usually −20°C. to 100° C. and preferably 0° C. to 25° C.

The reaction time varies depending on the reaction temperature, the rawmaterials, and the kinds of the reaction reagent or solvent used and isusually 10 minutes to 10 hours and preferably 30 minutes to 2 hours.

After the completion of the reaction, the target compound of thisprocess is collected from the reaction mixture according to the samemethod as in Process A.

The following Process C is for manufacturing a compound having formula(IV).

In the above formula, R¹ represents the same meaning as that describedabove. Y represents a halogen atom or a group represented by a formula—O—S(O)₂R^(c) (where R^(c) represents a methoxy group or a phenyl groupwhich may be substituted with one to three groups selected from thegroup consisting of C₁-C₆ alkyl groups which may be substituted with oneto three halogen atoms and halogen atoms).

Process C1 is for manufacturing a compound having formula (VII).

The process is conducted by a reaction between a compound having formula(VI) and a halogenating agent or a sulfonylating agent in a solvent inthe presence or absence of a base.

In the above reaction, any halogenating agent which is generally usedfor halogenating primary alcohols can be used without any limitation,and examples thereof include oxalyl chloride; thionylhalides such asthionylchloride and thionylbromide; phosphorus trihalides such asphosphorus trichloride and phosphorus tribromide; phosphoruspentahalides such as phosphorus pentachloride and phosphoruspentabromide; phosphorus oxyhalides such as phosphorus oxychloride andphosphorus oxybromide; Vilsmeier reagents such asN,N-dimethylchloroforminium chloride and N,N-dimethylbromoforminiumbromide; combinations of phosphines such as triphenylphosphine andhalogens or methane tetrahalides; and combinations of phosphines,azodicarboxylic acid esters, and metal halides such as a combination oftriphenylphosphine, diethyl azodicarboxylate, and lithium bromide.Oxalyl chloride is preferred, and a combination of oxalyl chloride and acatalytic amount of dimethylformamide is more preferred. The addition ofdimethylformamide enhances the reaction rate.

In the above reaction, any sulfonylating agent which is generally usedfor sulfonylation can be used without any limitation, and examplesthereof include sulfonyl halides such as methanesulfonyl chloride andp-toluenesulfonyl chloride, and sulfonic anhydride. Methanesulfonylchloride and p-toluenesulfonyl chloride are preferred.

The base used in the above reaction varies depending on, for example,the reagent used, but is not specifically limited. For example, organicbases such as imidazole, pyridine, triethylamine, and N-methylimidazolecan be used, and imidazole, pyridine, and triethylamine are preferred.

Examples of the solvent used in the above reaction include aliphatichydrocarbons such as hexane and heptane; aromatic hydrocarbons such astoluene and xylene; halogenated hydrocarbons such as dichloromethane and1,2-dichloroethane; esters such as ethyl acetate and butyl acetate;ethers such as tetrahydrofuran, diethyl ether, and t-butylmethyl ether;and amides such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide, andN,N-dimethylacetamide. Halogenated hydrocarbons are preferred, anddichloromethane is more preferred.

The reaction temperature varies depending on, for example, the rawmaterials, the reagent used, and the kind of the solvent and is usually−20° C. to 100° C. and preferably 0° C. to 25° C.

The reaction time varies depending on the reaction temperature, the rawmaterials, the reaction reagent, and the solvent used and is usually 10minutes to 12 hours and preferably 2 hours to 3 hours.

Process C2 is for manufacturing a compound having formula (IV).

The process is conducted by a reaction between a compound having formula(VII) and glycine in a solvent in the presence of a base.

The base used in the above reaction varies depending on, for example,the reagent used, but is not specifically limited. For example, organicbases such as imidazole, pyridine, triethylamine, N-methylimidazole, anddiisopropylethylamine are used, and triethylamine is preferred.

Examples of the solvent used in the above reaction include alcohols suchas methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,t-butanol, isoamyl alcohol, diethylene glycol, glycerine, octanol,cyclohexanol, and methyl cellosolve; ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, anddiethylene glycol dimethyl ether; water; and solvent mixtures such asmixtures of water and the above-mentioned organic solvents. Solventmixtures of ethers and water are preferred, and a solvent mixture oftetrahydrofuran and water is more preferred.

The reaction temperature varies depending on, for example, the rawmaterials, the reagent used, and the kind of the solvent used and isusually −20° C. to 100° C. and preferably 0° C. to 25° C.

The reaction time varies depending on the reaction temperature, the rawmaterials, the reaction reagent, and the kind of the solvent used and isusually 10 minutes to 24 hours and preferably 1 hour to 12 hours.

After the completion of the reaction, the target compound of thisprocess is collected from the reaction mixture according to the samemethod as in Process A.

The following Process D is an alternative process to Process C formanufacturing a compound having formula (IV).

In the above formula, R¹ represents the same meaning as that describedabove. R^(P) represents a carboxyl protecting group and is the same asthose described above.

Process D1 is for manufacturing a compound having a formula (IX) and isconducted by a reaction between a compound having a formula (VI) and acompound having a formula (VIII) in the presence of a condensing agentin a solvent in the presence or absence of a base.

Any condensing agent can be used in the above reaction without anylimitation, and examples thereof include azodicarboxylic acid di-loweralkyl ester-triphenylphosphines such as azodicarboxylic acid diethylester-triphenylphosphine; carbodiimide derivatives such asN,N′-dicyclohexylcarbodiimide (DCC) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); 2-halo-1-loweralkyl pyridinium halides such as 2-chloro-1-methylpyridinium iodide;diarylphosphorylazides such as diphenylphosphorylazide (DPPA);chloroformic acid esters such as ethyl chloroformate and isobutylchloroformate; phosphoryl chlorides such as diethyl phosphoryl chloride;imidazole derivatives such as N,N′-carbodiimidazole (CDI); benzotriazolederivatives such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and(1H-benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP); and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorphoriniumchloride (DMT-MM). DMT-MM is preferred.

The base used in the above reaction varies depending on, for example,the reagent used, but is not specifically limited. Examples of the baseinclude organic bases such as imidazole, pyridine, triethylamine,N-methylimidazole, and diisopropylethylamine. Triethylamine ispreferred.

Examples of the solvent used in the above reaction include halogenatedhydrocarbons such as dichloromethane and 1,2-dichloroethane; alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerine,octanol, cyclohexanol, and methyl cellosolve; ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, anddiethylene glycol dimethyl ether; and water. Alcohols and water arepreferred, and ethanol is more preferred.

The reaction temperature varies depending on, for example, the rawmaterials, the reagent used, and the kind of the solvent and is usually−20° C. to 100° C. and preferably 0° C. to 50° C.

The reaction time varies depending on the reaction temperature, the rawmaterials, the reaction reagent, and the kind of the solvent used and isusually 10 minutes to 24 hours and preferably 1 hour to 12 hours.

After the completion of the reaction, the target compound of thisprocess is collected from the reaction mixture according to the samemethod as in Process A.

Process D2 is for manufacturing a compound having a formula (IV) and isconducted by hydrolysis of a compound having formula (IX) in a solventin the presence of a base.

Examples of the base used in the above reaction include alkali metalcarbonates such as lithium carbonate, sodium carbonate, and potassiumcarbonate; alkali metal bicarbonates such as lithium hydrogen carbonate,sodium hydrogen carbonate, and potassium hydrogen carbonate; alkalimetal hydrides such as lithium hydride, sodium hydride, and potassiumhydride; alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, and potassium hydroxide; and alkali metal alkoxides such aslithium methoxide, sodium methoxide, sodium ethoxide, and potassiumt-butoxide. Alkali metal hydroxides are preferred, and lithium hydroxideand sodium hydroxide are more preferred.

Examples of the solvent used in the above reaction include ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane, and diethylene glycol dimethyl ether; lower alkylnitrites such as acetonitrile and propionitrile; amides such asformamide, N,N-dimethylformamide, N,N-dimethylacetamide, andhexamethylphosphoric acid triamide; lower alkyl alcohols such asmethanol, ethanol, propanol, and butanol; and water. Alcohols, ethers,and water are preferred, and ethanol is more preferred.

The reaction temperature varies depending on, for example, the rawmaterials, the reagent used, and the kind of the solvent and is usually0° C. to 100° C. and preferably 25° C. to 80° C.

The reaction time varies depending on the reaction temperature, the rawmaterials, the reaction reagent, and the kind of the solvent used and isusually 10 minutes to 12 hours and preferably 2 to 3 hours.

After the completion of the reaction, the target compound of thisprocess is collected from the reaction mixture according to the samemethod as in Process A.

The following Process E is an alternative process to process D2 ofProcess D for manufacturing a compound having formula (IV) from acompound having formula (IX).

In the above formula, R¹ is the same meaning as that described above.R^(P) represents protecting groups which can be deprotected with anacid, among the above-mentioned carboxyl protecting groups.

The “protecting groups which can be deprotected with an acid” arepreferably a THP (tetrahydropyranyl) group, a tetrahydrofuranyl group,an MEM (methoxyethoxymethyl) group, a BOM (benzyloxymethyl) group, atertiary butyl (t-butyl) group, a diphenylmethyl group, a9-anthrylmethyl group, and a 5-dibenzoylsuberyl group.

Process E1 is for manufacturing a compound having formula (IV) and isconducted by hydrolysis of a compound having formula (IX) in a solventin the presence of an acid.

Examples of the acid used in the above reaction include Bronsted acids,for example, inorganic acids, such as hydrochloric acid, hydrobromicacid, sulfuric acid, perchloric acid, and phosphoric acid, and organicacids, such as acetic acid, formic acid, oxalic acid, methanesulfonicacid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroaceticacid, and trifluoromethanesulfonic acid; Lewis acids such as zincchloride, tin tetrachloride, boron trichloride, boron trifluoride, andboron tribromide; and acidic ion-exchange resins. Inorganic acids andorganic acids are preferred, and trifluoroacetic acid is more preferred.

Examples of the solvent used in the above reaction include aliphatichydrocarbons such as hexane, heptane, ligroin, and petroleum ether;aromatic hydrocarbons such as toluene, benzene, and xylene; halogenatedhydrocarbons such as dichloromethane and 1,2-dichloroethane; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane, and diethylene glycol dimethyl ether; lower alkylnitrites such as acetonitrile and propionitrile; and amides such asformamide, N,N-dimethylformamide, N,N-dimethylacetamide, andhexamethylphosphoric acid triamide. Halogenated hydrocarbons arepreferred, and dichloromethane is more preferred.

The reaction temperature varies depending on, for example, the rawmaterials, the reagent used, and the kind of the solvent and is usually0 to 100° C. and preferably 0 to 50° C.

The reaction time varies depending on the reaction temperature, the rawmaterials, the reaction reagent, and the kind of the solvent used and isusually 10 minutes to 6 hours and preferably 1 to 3 hours.

After the completion of the reaction, the target compound of thisprocess is collected from the reaction mixture according to the samemethod as in Process A.

The following Process F is for manufacturing a compound having formula(VI′) which can be used as a compound having formula (VI) in Process Cor D.

In the above formula, R^(P) represents the same meaning as that in theabove-mentioned Process D or E, and R^(x) represents a group selectedfrom the group consisting of C₁-C₆ alkoxy groups which may besubstituted with one group or more than one group selected fromsubstituent group β, C₁-C₆ haloalkoxy groups, C₁-C₆ alkoxy C₁-C₆ alkoxygroups which may be substituted with one group or more than one groupselected from substituent group β, C₁-C₆ alkenyloxy groups which may besubstituted with one group or more than one group selected fromsubstituent group β, C₁-C₆ alkynyloxy groups which may be substitutedwith one group or more than one group selected from substituent group β,C₃-C₆ cycloalkyloxy groups, 3- to 6- membered groups heterocyclyloxygroups, C₆-C₁₀ aryloxy groups which may be substituted with one group ormore than one group selected from substituent group γ, C₁-C₆ alkylthiogroups which may be substituted with one group or more than one groupselected from substituent group β, and C₁-C₆ haloalkylthio groups, amonggroups selected from substituent group α.

Process F1 is for manufacturing a compound having formula (XII) and isconducted by a reaction between a compound having formula (X) and acompound having formula (XI) in a solvent using a Mitsunobu reagent orthe like.

The Mitsunobu reagent or the like used in the above reaction ispreferably a combination of an azo compound, for example, adiazodicarboxylic acid lower alkyl ester such as diethylazodicarboxylate or diisopropyl azodicarboxylate or an azodicarbonylsuch as 1,1′-(azodicarbony)dipiperidine and a phosphine, for example, atriarylphosphine such as triphenylphosphine or a tri-lower alkylphosphine such as tributylphosphine; or a tributyl phosphoranylideneacetonitrile, more preferably a combination of a diazodicarboxylic acidlower alkyl ester and a triarylphosphine, or tributyl phosphoranylideneacetonitrile, and particularly more preferably a combination of diethylazodicarboxylate and triphenylphosphine, or tributyl phosphoranylideneacetonitrile.

The Case that the Mitsunobu Reagent or the Like is TributylPhosphoranylidene Acetonitrile

Examples of the solvent used include aliphatic hydrocarbons such ashexane, heptane, ligroin, and petroleum ether; aromatic hydrocarbonssuch as toluene, benzene, and xylene; halogenated hydrocarbons such asdichloromethane and 1,2-dichloroethane; and ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, anddiethylene glycol dimethyl ether. Aromatic hydrocarbons are preferred,and toluene is more preferred.

The reaction temperature varies depending on, for example, the rawmaterials, the reagent used, and the kind of the solvent and is usually0 to 150° C. and preferably 50 to 120° C.

The reaction time varies depending on the reaction temperature, the rawmaterials, the reaction reagent, and the kind of the solvent used and isusually 30 minutes to 12 hours and preferably 2 to 5 hours.

(2) The Case that the Mitsunobu Reagent or the Like is a Combination ofan Azo Compound and a Phosphine

Examples of the solvent used include aliphatic hydrocarbons such ashexane, heptane, ligroin, and petroleum ether; aromatic hydrocarbonssuch as toluene, benzene, and xylene; halogenated hydrocarbons such asdichloromethane and 1,2-dichloroethane; and ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, anddiethylene glycol dimethyl ether. Ethers are preferred, andtetrahydrofuran is more preferred.

The reaction temperature varies depending on, for example, the rawmaterials, the reagent used, and the kind of the solvent and is usually−20 to 80° C. and preferably 0 to 50° C.

The reaction time varies depending on the reaction temperature, the rawmaterials, the reaction reagent, and the kind of the solvent used and isusually 30 minutes to 24 hours and preferably 1 to 3 hours.

After the completion of the reaction, the target compound of thisprocess is collected from the reaction mixture according to the samemethod as in Process A.

Process F2 is for manufacturing a compound having a formula (VI′) and isconducted by hydrolysis of a compound having formula (XII) in a solventin the presence of a base or an acid by the same process of process D2of Process D or process E1 of Process E.

(Description of Usefulness)

The amido derivative which is an active ingredient of the drug of thepresent invention or its pharmacologically acceptable salt is low intoxicity and is excellent in bone resorption-suppressing activity.Therefore, the drug of the present invention is particularly valuable asa prophylactic or therapeutic agent (in particular, therapeutic agent)for osteoporosis.

When the compound having Formula (I), which is an active ingredient ofthe drug of the present invention, or its pharmacologically acceptablesalt is used as the above-mentioned prophylactic or therapeutic agent(in particular, therapeutic agent), the compound or the salt itself or amixture with an optional pharmacologically acceptable filler, diluent,or the like can be administered, for example, orally as a tablet, acapsule, granules, powder, or syrup; or parenterally as an injection ora suppository.

These formulations are prepared by widely known methods using additivessuch as fillers (for example, organic fillers: sugar derivatives such aslactose, white sugar, glucose, mannitol, and sorbitol; starchderivatives such as corn starch, potato starch, α-starch, and dextrin;cellulose derivatives such as crystal cellulose; gum arabic; dextran;and pullulan, and inorganic fillers: silicate derivatives such as lightanhydrous silicic acid, synthetic aluminum silicate, calcium silicate,and magnesium aluminometasilicate; phosphates such as calcium hydrogenphosphate; carbonates such as calcium carbonate; and sulfates such ascalcium sulfate), lubricants (for example, stearic acid, stearic acidmetal salts such as calcium stearate, and magnesium stearate; talc;colloidal silica; waxes such as bee gum and spermaceti; boric acid;adipic acid; sulfuric acid salts such as sodium sulfate; glycol; fumaricacid; sodium benzoate; D,L-leucine; fatty acid sodium salts;laurylsulfuric acid salts such as sodium laurylsulfate and magnesiumlaurylsulfate; silic acids such as silicic anhydride and silicatehydrate; and the above-mentioned starch derivatives), binders (forexample, hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, macrogol, and the same compounds as theabove-mentioned fillers), disintegrating agents (for example, cellulosederivatives such as low-substituted hydroxypropylcellulose,carboxylmethylcellulose, carboxylmethylcellulose calcium, andinternally-crosslinked carboxylmethylcellulose sodium; and chemicallymodified starch/cellulose such as carboxylmethyl starch, carboxylmethylstarch sodium, and crosslinked polyvinylpyrrolidone), stabilizers (forexample, paraoxybenzoic acid esters such as methylparaben andpropylparaben; alcohols such as chlorobutanol, benzylalcohol, andphenylethylalcohol; benzalkonium chloride; phenols such as phenol andcresol; thimerosal; dehydroacetic acid; and sorbic acid), flavoringagents (for example, sweeteners, acidifiers, and flavors which areusually used), and diluents.

The dosage and administration regimen vary depending on, for example,the symptom and the age. Usually, the formulation is administered asfollows:

For oral administration, the dose per administration is 0.001 to 100mg/kg and preferably 0.01 to 10 mg/kg.

In intravenous administration, the dose per administration is 0.0001 to10 mg/kg and preferably 0.001 to 1 mg/kg.

The administration frequency and the administration interval varydepending on the disease to be treated and its severity or the purpose,i.e., therapeutic use or prophylactic use, and are usually one to threetimes a day or one to six times weekly to monthly. The pharmaceuticalcomposition according to the present invention has satisfactory physicalstability, bioabsorption, and pharmacokinetics and thereby has anexcellent advantage as the administration frequency may be low.

Advantages of the Invention

The present inventors have conducted intensive studies on drugs havingexcellent blood calcium concentration-decreasing activity and bone massdecrease-suppressing activity and have found drugs comprising thecompounds having Formula (I) of the present invention.

The compounds having Formula (I) of the present invention are low intoxicity and have excellent bone resorption-suppressing activity andthereby blood calcium concentration-decreasing activity and bone massdecrease-suppressing activity. Therefore, the compound is valuable as aprophylactic or therapeutic agent (in particular, therapeutic agent) forthe above-mentioned bone metabolic diseases.

BEST MODE FOR CARRYING OUT THE INVENTION Examples

The present invention will now be further described in detail withreference to Examples and Test Examples, but is not limited to them.

Example 1N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamideExemplary Compound No. 1-144

(1a) N-(4-Hydroxybenzoyl)glycine tert-butyl ester

Oxalyl chloride (8.7 mL, 99.7 mmol) and several drops ofN,N-dimethylformaldehyde (hereinafter DMF) were added to a solution ofdichloromethane (40 mL) containing 4-benzyloxybenzoic acid (11.1 g, 48.6mmol) under ice-cooling. The mixture was stirred at room temperature for2 hours, and then the solvent was evaporated. The resulting residue wasdissolved in dichloromethane (100 mL), and then glycine tert-butyl esterhydrochloride (8.20 g, 48.9 mmol) and N-ethyl-N,N-diisopropylamine (21mL, 120 mmol) were added thereto under ice-cooling. The mixture wasstirred at room temperature for 19 hours, and then water was addedthereto to terminate the reaction. The mixture was extracted withdichloromethane twice, and the organic layers were combined andconcentrated. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate, 9:1 to 2:1, v/v) to giveN-[4-(benzyloxy)benzoyl]glycine tert-butyl ester. All the given esterwas dissolved in methanol (165 mL), and 20% palladium hydroxide-carbon(926 mg) was added thereto. The mixture was vigorously stirred under ahydrogen atmosphere at room temperature for 3.5 hours. The reactionmixture was filtered through Celite and then concentrated to give 12.2 gof the title compound (colorless crystalline solid, yield:quantitative).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.97 (1H, s), 8.54 (1H, brt, J=6 Hz), 7.70 (2H, d, J=9 Hz), 6.78 (2H, d,J=9 Hz), 3.83 (2H, d, J=6 Hz), 1.41 (9H, s).

(1b) N-{4-[2-(4-Methoxyphenyl)ethoxy]benzoyl}glycine

(Tributyl phosphoranylidene)acetonitrile (428 μL, 1.50 mmol) was addedto a solution of toluene (7 mL) containing N-(4-hydroxybenzoyl)glycinetert-butyl ester (264 mg, 1.05 mmol) prepared in Example 1 (1a) and2-(4-methoxyphenyl)ethanol (176 mg, 1.16 mmol). The mixture was stirredat 100° C. for 3.5 hours, and then water was added thereto. The mixturewas extracted with ethyl acetate. The organic layers were combined,washed with water and saturated brine, and dried over anhydrousmagnesium sulfate. Then, the solvent was evaporated. The resultingresidue was purified by silica gel column chromatography (hexane tohexane:ethyl acetate, 6:1, 4:1, and 3:1, v/v) to give an oily substance(358 mg). To a solution of dichloromethane (1 mL) containing this oilysubstance (358 mg, 0.929 mmol), trifluoroacetic acid (0.5 mL) was added.The mixture was stirred at room temperature for 1 hour, and then thesolvent was evaporated. Diisopropyl ether was added to the resultingresidue to suspend it. The produced precipitate was collected byfiltration and was washed with diisopropyl ether to give 248 mg of thetitle compound (colorless crystalline solid, yield: 72%).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

12.50 (1H, brs), 8.67 (1H, t, J=5 Hz), 7.83 (2H, d, J=8 Hz), 7.24 (2H,d, J=8 Hz), 7.00 (2H, d, J=8 Hz), 6.87 (2H, d, J=8 Hz), 4.20 (2H, t, J=6Hz), 3.89 (2H, d, J=5 Hz), 3.72 (3H, s), 2.98 (2H, t, J=6 Hz).

(1c)(4Z)-4-(4-Chlorobenzylidene)-2-{4-[2-(4-methoxyphenyl)ethoxy]phenyl}-1,3-oxazol-5(4H)-one

A mixture of N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg,1.00 mmol) prepared in Example 1 (1b), 4-chlorobenzaldehyde (148 mg,1.05 mmol), sodium acetate (111 mg, 1.35 mmol), and acetic anhydride(467 μL, 5.00 mmol) was stirred at 120° C. for 20 minutes, and thenwater was added thereto to terminate the reaction. Then, continuously,the mixture was vigorously stirred until the mixture was cooled to roomtemperature. The deposited precipitate was collected by filtration,washed with water and hexane, and dried by heating under reducedpressure to give 376 mg of the title compound (yellow powder, yield:87%).

Hereinafter, the compound obtained in this cyclizing reaction is calledan oxazolone.

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.11 (2H, d, J=9 Hz), 8.09 (2H, d, J=9 Hz), 7.42 (2H, d, J=9 Hz), 7.20(2H, d, J=8 Hz), 7.09 (1H, s), 6.99 (2H, d, J=9 Hz), 6.86 (2H, d, J=8Hz), 4.22 (2H, t, J=7 Hz), 3.80 (3H, s), 3.08 (2H, t, J=7 Hz).

(1d)N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide

2-Aminoethanol (18 μL, 0.30 mmol) was added to a solution of ethanol(0.7 mL) containing(4Z)-4-(4-chlorobenzylidene)-2-{4-[2-(4-methoxyphenyl)ethoxy]phenyl}-1,3-oxazol-5(4H)-oneprepared in Example 1 (1c) (108 mg, 0.25 mmol). The mixture was stirredat 60° C. for 3 hours. The solvent was evaporated, and the residue waspurified by thin layer chromatography for separation (ethylacetate:methanol, 30:1, v/v, developed three times) to give 88 mg of thetitle compound (white amorphous solid, yield: 71%).

MS (FAB) m/z: 495 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.75 (1H, brs), 8.06 (1H, t, J=5 Hz), 7.94 (2H, d, J=8 Hz), 7.53 (2H, d,J=8 Hz), 7.39 (2H, d, J=7 Hz), 7.25 (2H, d, J=7 Hz), 7.14 (1H, s), 7.04(2H, d, J=8 Hz), 6.88 (2H, d, J=7 Hz), 4.63 (1H, t, J=6 Hz), 4.23 (2H,t, J=7 Hz), 3.73 (3H, s), 3.44 (2H, q, J=6 Hz), 3.23 (2H, q, J=6 Hz),2.99 (2H, t, J=6 Hz).

Example 2N-((Z)-2-[4-(Difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide(Exemplary Compound No. 1-131)

The same reaction as in Example (1c) was conducted usingN-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg) prepared inExample 1 (1b) and 4-(difluoromethoxy)benzaldehyde (139 μL) to give thecorresponding oxazolone (334 mg). Then, the same reaction as in Example1 (1d) was conducted using 121 mg of this oxazolone to give 114 mg ofthe title compound (white amorphous solid).

MS (FAB) m/z: 527 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.89 (1H, brs), 7.77 (2H, d, J=9 Hz), 7.37 (2H, d, J=9 Hz), 7.20 (2H, d,J=9 Hz), 7.05 (2H, d, J=9 Hz), 7.00 (1H, s), 6.91 (2H, d, J=9 Hz), 6.87(2H, d, J=9 Hz), 6.77 (1H, t, J=6 Hz), 6.49 (1H, t, J=74 Hz), 4.17 (2H,t, J=7 Hz), 3.80 (3H, s), 3.77 (2H, t, J=5 Hz), 3.49 (2H, q, J=5 Hz),3.06 (2H, t, J=7 Hz).

Example 3N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamide(Exemplary Compound No. 1-132)

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg) prepared inExample 1 (1b) and 4-(trifluoromethoxy)benzaldehyde (150 μL) to give thecorresponding oxazolone (366 mg). Then, the same reaction as in Example1 (1d) was conducted using 160 mg of this oxazolone to give 126 mg ofthe title compound (white powder).

mp: 139 to 141° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.80 (1H, brs), 8.08 (1H, t, J=5 Hz), 7.95 (2H, d, J=8 Hz), 7.64 (2H, d,J=7 Hz), 7.33 (2H, d, J=8 Hz), 7.25 (2H, d, J=7 Hz), 7.17 (1H, s), 7.04(2H, d, J=8 Hz), 6.88 (2H, d, J=8 Hz), 4.64 (1H, t, J=5 Hz), 4.23 (2H,t, J=6 Hz), 3.73 (3H, s), 3.46 (2H, q, J=6 Hz), 3.24 (2H, q, J=6 Hz),3.00 (2H, t, J=6 Hz).

Example 4N-((Z)-2-[4-(2,2-Difluoroethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide(Exemplary Compound No. 1-134)

(4a) 4-(2,2-Difluoroethoxy)benzaldehyde

With reference to the document (J. Med. Chem., (1994), 37, 3977-3985),sodium hydride (3.36 g, 55%, 77.1 mmol) was added to a solution of DMF(100 mL) containing 2,2-difluoroethanol (5.75 g, 70.1 mmol) over 5minutes under nitrogen gas flow under ice-cooling. The mixture wasstirred at the same temperature for 10 minutes, and then a solution ofDMF (40 mL) containing 4-fluorobenzaldehyde (9.56 g, 77.0 mmol) wasadded dropwise thereto over 5 minutes. The mixture was stirred at roomtemperature for 4 hours and was then poured into ice water (500 mL). Theresulting mixture was extracted with ether:hexane (300 mL, 1:1, v/v)three times. The extracted organic layer was washed with water (300 mL)three times and then with saturated brine, and was dried over anhydrousmagnesium sulfate. Then, the solvent was evaporated to give a crudeproduct. An ether/hexane mixture solution (20 mL, 1:10, v/v) was addedto the crude product, and the supernatant fluid was removed. Thisprocedure was repeated four times in total to wash the crystals to give10.1 g of the title compound (colorless crystalline solid, yield: 77%).

¹H-nuclear magnetic resonance spectrum (500 MHz, CDCl₃) δ ppm:

9.92 (1H, s), 7.87 (2H, d, J=8 Hz), 7.04 (2H, d, J=8 Hz), 6.13 (1H, tt,J=55 Hz, 4 Hz), 4.27 (2H, td, J=13 Hz, 4 Hz).

(4b)N-((Z)-2-[4-(2,2-Difluoroethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg) prepared inExample 1 (1b) and 4-(2,2-difluoroethoxy)benzaldehyde (196 mg) preparedin Example 4 (4a) to give the corresponding oxazolone (306 mg). Then,the same reaction as in Example 1 (1d) was conducted using 158 mg ofthis oxazolone to give 144 mg of the title compound (white powder).

mp: 172 to 174° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.69 (1H, brs), 7.96 (2H, d, J=8 Hz), 7.93 (1H, t, J=5 Hz), 7.51 (2H, d,J=8 Hz), 7.25 (2H, d, J=7 Hz), 7.20 (1H, s), 7.04 (2H, d, J=8 Hz), 6.97(2H, d, J=8 Hz), 6.88 (2H, d, J=7 Hz), 6.36 (1H, tt, J=55 Hz, 3 Hz),4.63 (1H, t, J=7 Hz), 4.30 (2H, td, J=14 Hz, 3 Hz), 4.23 (2H, t, J=7Hz), 3.73 (3H, s), 3.43 (2H, q, J=6 Hz), 3.22 (2H, q, J=6 Hz), 3.00 (2H,t, J=7 Hz).

Example 5N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide(Exemplary Compound No. 1-138)

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg) prepared inExample 1 (1b) and 4-cyclopropylbenzaldehyde (which is the compounddisclosed in Tetrahedron Lett., (2002), 43, 6987-6990, 154 mg) to givethe corresponding oxazolone (300 mg). Then, the same reaction as inExample 1 (1d) was conducted using 154 mg of this oxazolone to give 155mg of the title compound (white amorphous solid).

MS (FAB) m/z: 501 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.79 (2H, d, J=9 Hz), 7.71 (1H, brs), 7.28 (2H, d, J=8 Hz), 7.20 (2H, d,J=8 Hz), 7.05 (1H, s), 7.02 (2H, d, J=8 Hz), 6.93 (2H, d, J=9 Hz), 6.87(2H, d, J=9 Hz), 6.65 (1H, t, J=5 Hz), 4.18 (2H, t, J=7 Hz), 3.80 (3H,s), 3.78 (2H, t, J=5 Hz), 3.50 (2H, q, J=5 Hz), 3.06 (2H, t, J=7 Hz),1.89-1.83 (1H, m), 1.01-0.96 (2H, m), 0.71-0.67 (2H, m).

Example 6N-((Z)-2-[4-(Cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide(Exemplary Compound No. 1-130)

(6a) 1-Bromo-4-(2-chloroethoxy)benzene

With reference to the document (J. Org. Chem., (2002), 67, 1093-1101),potassium carbonate (83.0 g, 600 mmol) was added to a solution of DMF(500 mL) containing 4-bromophenol (50.4 g, 291 mmol) at roomtemperature. The mixture was stirred at the same temperature for 30minutes, and then 2-chloroethyl 4-methylbenzenesulfonate (70.2 g, 299mmol) was added thereto. The mixture was stirred at 50° C. for 24 hours.The reaction solution was cooled to 10° C., and water (500 mL) was addedthereto to precipitate a white solid. This white solid was collected byfiltration, washed with water (500 mL), and dried at 50° C. underreduced pressure to give 58.6 g of the title compound (yield: 86%).

mp: 54 to 56° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.39 (2H, d, J=9 Hz), 6.81 (2H, d, J=9 Hz), 4.20 (2H, t, J=6 Hz), 3.80(2H, t, J=6 Hz).

(6b) 1-Bromo-4-(vinyloxy)benzene

Tert-Butoxypotassium (33.7 g, 300 mmol) was added to a solution oftetrahydrofuran (hereinafter THF) (250 mL) containing1-bromo-4-(2-chloroethoxy)benzene (58.6 g, 249 mmol) prepared in Example6 (6a) over 10 minutes at −10° C. The mixture was stirred at roomtemperature for 21 hours, and water (500 mL) was added thereto. Theresulting mixture was extracted with methyl tert-butyl ether (200 mL,150 mL) twice. The organic layers were combined, washed with saturatedbrine (100 mL) twice, and dried over anhydrous magnesium sulfate. Then,the solvent was evaporated. The resulting residue was dissolved inhexane (100 mL), and the precipitated insoluble substance was removed byfiltration. The insoluble substance was further washed with hexane (5mL) five times. The filtrates were combined, concentrated, and purifiedby silica gel column chromatography (hexane) to give 39.0 g of the titlecompound (colorless oil, yield: 79%).

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.43 (2H, d, J=9 Hz), 6.89 (2H, d, J=9 Hz), 6.59 (1H, dd, J=14 Hz, 6Hz), 4.78 (1H, dd, J=14 Hz, 2 Hz), 4.47 (1H, dd, J=6 Hz, 2 Hz).

(6c) 4-(Cyclopropyloxy)benzaldehyde

With reference to the document (Tetrahedron Lett., (1998), 39,8621-8624), the following cyclopropanization was conducted. Diethyl zinc(1.0 M hexane solution, 250 mL, 250 mmol) was added to dichloromethane(250 mL), and a solution of dichloromethane (120 mL) containingtrifluoroacetic acid (19.2 mL, 249 mmol) was added thereto underice-cooling over 100 minutes. The mixture was further stirred for 1hour. Then, a solution of dichloromethane (100 mL) containingchloroiodomethane (20.1 mL, 250 mmol) was added thereto underice-cooling over 40 minutes, and a solution of dichloromethane (120 mL)containing 1-bromo-4-(vinyloxy)benzene (32.8 g, 165 mmol) prepared inExample 6 (6b) was further added thereto at the same temperature over 20minutes. The mixture was stirred at room temperature for 1.5 hours.Then, 0.1 N hydrochloric acid (400 mL) was added to the reactionsolution. The mixture was stirred for 30 minutes, filtered throughCelite, and washed with hexane (200 mL). The filtrate and the hexanewashing solution were combined. The organic layer was washed with 0.1Nhydrochloric acid (100 mL) and then with saturated brine (100 mL)containing about 1 g of sodium sulfite twice. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedto give 36.0 g of 1-bromo-4-(cyclopropyloxy)benzene (yellow oil).

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.37 (2H, d, J=9 Hz), 6.93 (2H, d, J=9 Hz), 3.72-3.68 (1H, m), 0.79-0.73(4H, m).

To a solution of THF (350 mL) containing this crude product (36.0 g, 165mmol), n-butyllithium (116 mL, 1.56 M hexane solution, 181 mmol) wasadded at −66° C. over 40 minutes under a nitrogen atmosphere. Themixture was stirred at the same temperature for 1 hour. Then, DMF (23.6g, 323 mmol) was added dropwise to the reaction solution over 12minutes. The mixture was stirred at the same temperature for 30 minutesand left standing at room temperature overnight, and then a saturatedammonium chloride aqueous solution (150 mL) was added dropwise theretoover 5 minutes. The organic layer was separated and was washed with asaturated ammonium chloride aqueous solution (100 mL) and saturatedbrine (100 mL). The washing solution was combined and was extracted withhexane (200 mL). All organic layers were combined and dried overanhydrous magnesium sulfate. The solvent was evaporated, and theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate, 9:1, v/v) to give 23.3 g of the title compound(light yellow oil, yield: 87%).

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

9.87 (1H, s), 7.82 (2H, d, J=9 Hz), 7.14 (2H, d, J=9 Hz), 3.83-3.79 (1H,m), 0.87-0.81 (4H, m).

(6d)N-((Z)-2-[4-(Cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg) prepared inExample 1 (1b) and 4-(cyclopropyloxy)benzaldehyde (170 mg) prepared inExample 6 (6c) to give the corresponding oxazolone (304 mg). Then, thesame reaction as in Example 1 (1d) was conducted using 159 mg of thisoxazolone to give 159 mg of the title compound (white amorphous solid).

MS (FAB) m/z: 517 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.81 (2H, d, J=9 Hz), 7.68 (1H, brs), 7.35 (2H, d, J=9 Hz), 7.21 (2H, d,J=8 Hz), 7.10 (1H, s), 7.00 (2H, d, J=9 Hz), 6.94 (2H, d, J=9 Hz), 6.87(2H, d, J=8 Hz), 6.64 (1H, t, J=6 Hz), 4.19 (2H, t, J=7 Hz), 3.80 (3H,s), 3.78 (2H, t, J=5 Hz), 3.71 (1H, sept, J=3 Hz), 3.51 (2H, q, J=5 Hz),3.06 (2H, t, J=7 Hz), 0.78-0.75 (4H, m).

Example 7N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-methoxyphenyl)ethoxy]benzamideExemplary Compound No. 1-129

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (248 mg) prepared inExample 1 (1b) and 4-isopropoxybenzaldehyde (131 μL) to give thecorresponding oxazolone (227 mg). Then, the same reaction as in Example1 (1d) was conducted using all this oxazolone to give 122 mg of thetitle compound (white amorphous solid).

MS (FAB) m/z: 519 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.67 (1H, brs), 7.97 (2H, d, J=8 Hz), 7.89 (1H, brt, J=5 Hz), 7.47 (2H,d, J=8 Hz), 7.26 (2H, d, J=8 Hz), 7.18 (1H, s), 7.05 (2H, d, J=8 Hz),6.89 (2H, d, J=8 Hz), 6.86 (2H, d, J=8 Hz), 4.64-4.58 (2H, m), 4.23 (2H,t, J=7 Hz), 3.73 (3H, s), 3.43 (2H, q, J=6 Hz), 3.22 (2H, q, J=6 Hz),3.00 (2H, t, J=7 Hz), 1.23 (6H, d, J=6 Hz).

Example 8N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(methylthio)phenyl]vinyl}-4-[2-(4-methoxyphenyl)ethoxy]benzamideExemplary Compound No. 1-141

The same reaction as in Example 1 (I c) was conducted usingN-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg) prepared inExample 1 (1b) and 4-(methylthio)benzaldehyde (140 μL) to give thecorresponding oxazolone (342 mg). Then, the same reaction as in Example1 (1d) was conducted using 156 mg of this oxazolone to give 134 mg ofthe title compound (white powder).

mp: 61 to 63° C.;

¹H-nuclear magnetic resonance spectrum (500 MHz, CDCl₃) δ ppm:

7.79-7.78 (3H, m), 7.30 (2H, d, J=9 Hz), 7.21 (2H, d, J=9 Hz), 7.16 (2H,d, J=9 Hz), 7.02 (1H, s), 6.92 (2H, d, J=9 Hz), 6.87 (2H, d, J=9 Hz),6.70 (1H, t, J=6 Hz), 4.18 (2H, t, J=7 Hz), 3.80 (3H, s), 3.77 (2H, t,J=5 Hz), 3.50 (2H, q, J=5 Hz), 3.06 (2H, t, J=7 Hz), 2.45 (3H, s).

Example 94-(2-Cyclopropylethoxy)-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-68

(9a) 4-(2-Cyclopropylethoxy)benzoic acid

Methyl 4-hydroxybenzoate (8.83 g, 58.0 mmol), 2-cyclopropylethanol (5.13g, 59.6 mmol), and triphenylphosphine (15.7 g, 59.9 mmol) were dissolvedin THF (250 mL). Then, diethyl azodicarboxylate (29.8 mL, 40% toluenesolution, 59.6 mmol) was added thereto under ice-cooling while stirring.The mixture was stirred at room temperature for 2 days, and then water(200 mL) was added to the reaction solution. The resulting mixture wasextracted with ethyl acetate twice. The organic layers were combined,washed with saturated brine, and dried over anhydrous magnesium sulfate,and then the solvent was evaporated. The resulting residue was dissolvedin diethyl ether. The produced precipitate was removed by filtration,and diethyl ether was evaporated. This filtration procedure was repeatedtwice, and the residue was purified by silica gel column chromatography(hexane:ethyl acetate, 20:1, v/v) to give an oily substance (13.2 g).All this oily substance was dissolved in ethanol (200 mL), and a 2 Mlithium hydroxide aqueous solution (60 mL, 120 mmol) was added thereto.The mixture was stirred at 60° C. for 50 minutes, and then 10%hydrochloric acid (40 mL) was added thereto under ice-cooling. Theresulting mixture was extracted with ethyl acetate twice. The organiclayers were combined, washed with saturated brine, and dried overanhydrous magnesium sulfate. Then, the solvent was evaporated. Theresulting residue was suspended in diisopropyl ether, and theprecipitate was collected by filtration and dried under reduced pressureto give 9.28 g of the title compound (powder, yield: 78%).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

12.6 (1H, s), 7.88 (2H, d, J=9 Hz), 7.02 (2H, d, J=9 Hz), 4.10 (2H, t,J=7 Hz), 1.64 (2H, q, J=7 Hz), 0.88-0.79 (1H, m), 0.46-0.42 (2H, m),0.15-0.11 (2H, m).

(9b) N-[4-(2-Cyclopropylethoxy)benzoyl]glycine

Oxalyl chloride (8.64 mL, 99.0 mmol) and one drop of DMF were added to asolution of dichloromethane (30 mL) containing4-(2-cyclopropylethoxy)benzoic acid (9.28 g, 45.0 mmol) prepared inExample 9 (9a) under ice-cooling. The mixture was stirred at roomtemperature for 1.75 hours, and the solvent was evaporated. Then, theresulting residue was suspended in THF (3 mL). This suspension addeddropwise to a 50% THF aqueous solution (120 mL) containing glycine (4.41g, 58.7 mmol) and triethylamine (15.7 mL, 112 nmol) under ice-cooling.The mixture was stirred at room temperature for 1.5 hours, and then 10%hydrochloric acid (40 mL) was added thereto under ice-cooling. Theproduced precipitate was collected by filtration, washed with water, anddried by heating under reduced pressure to give 11.4 g of the titlecompound (powder, yield: 97%).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

12.5 (1H, brs), 8.64 (1H, brt, J=6 Hz), 7.81 (2H, d, J=9 Hz), 6.98 (2H,d, J=9 Hz), 4.07 (2H, t, J=7 Hz), 3.88 (2H, d, J=6 Hz), 1.63 (2H, q, J=7Hz), 0.88-0.78 (1H, m), 0.46-0.42 (2H, m), 0.15-0.11 (2H, m).

(9c)(4Z)-4-(4-Cyclopropylbenzylidene)-2-[4-(2-cyclopropylethoxy)phenyl]-1,3-oxazol-5(4H)-one

A mixture of N-[4-(2-cyclopropylethoxy)benzoyl]glycine (184 mg, 0.699mmol) prepared in Example 9 (9b), 4-cyclopropylbenzaldehyde (113 mg,0.769 mmol) prepared in Example 5, sodium acetate (75 mg, 0.909 mmol),and acetic anhydride (660 μL, 6.99 mmol) was stirred at 120° C. for 30minutes and was then allowed to cool to room temperature. Hexane (2 mL)and water (4 mL) were added to the resulting solidified product whichwas washed by ultrasonic vibration. The precipitate was collected byfiltration, washed with water and hexane, and dried by heating underreduced pressure to give 196 mg of the title compound (white powder,yield: 74%).

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.12 (2H, d, J=9 Hz), 8.10 (2H, d, J=8 Hz), 7.16 (1H, s), 7.15 (2H, d,J=8 Hz), 7.03 (2H, d, J=9 Hz), 4.14 (2H, t, J=7 Hz), 1.99-1.93 (1H, m),1.73 (2H, q, J=6 Hz), 1.10-1.05 (2H, m), 0.93-0.83 (1H, m), 0.83-0.79(2H, m), 0.55-0.50 (2H, m), 0.17-0.14 (2H, m).

(9d)4-(2-Cyclopropylethoxy)-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide

2-Aminoethanol (20 μL, 0.33 mmol) was added to a solution of ethanol(1.6 mL) containing(4Z)-4-(4-cyclopropylbenzylidene)-2-[4-(2-cyclopropylethoxy)phenyl]-1,3-oxazol-5(4H)-one(95 mg, 0.25 mmol) prepared in Example 9 (9c). The mixture was stirredat 60° C. for 1 hour, and then the solvent was removed. The residue waswashed with hexane:ethyl acetate (3:1, v/v). The precipitate wascollected by filtration and dried under reduced pressure to give 95 mgof the title compound (white powder, yield: 86%).

mp: 195 to 200° C. (dec.).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.67 (1H, brs), 7.95-7.91 (3H, m), 7.39 (2H, d, J=8 Hz), 7.15 (1H, brs),7.02 (2H, d, J=9 Hz), 7.00 (2H, d, J=9 Hz), 4.62 (1H, t, J=5 Hz), 4.10(2H, t, J=7 Hz), 3.43 (2H, q, J=6 Hz), 3.22 (2H, q, J=6 Hz), 1.90-1.83(1H, m), 1.65 (2H, q, J=7 Hz), 0.95-0.91 (2H, m), 0.89-0.80 (1H, m),0.68-0.64 (2H, m), 0.47-0.43 (2H, m), 0.16-0.12 (2H, m).

Example 104-(2-Cyclopropylethoxy)-N-((Z)-2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-61

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-cyclopropylethoxy)benzoyl]glycine (150 mg) prepared in Example 9(9b) and 4-(difluoromethoxy)benzaldehyde (83 μL) to give thecorresponding oxazolone (188 mg). Then, the same reaction as in Example9 (9d) was conducted using 90 mg of this oxazolone to give 76 mg of thetitle compound (white powder).

mp: 153 to 155° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.72 (1H, brs), 8.00 (1H, brt, J=6 Hz), 7.93 (2H, d, J=9 Hz), 7.56 (2H,d, J=9 Hz), 7.23 (1H, t, J=74 Hz), 7.16 (1H, s), 7.12 (2H, d, J=9 Hz),7.02 (2H, d, J=9 Hz), 4.62 (1H, t, J=5 Hz), 4.10 (2H, t, J=7 Hz), 3.43(2H, q, J=6 Hz), 3.22 (2H, q, J=6 Hz), 1.64 (2H, q, J=7 Hz), 0.88-0.81(1H, m), 0.47-0.43 (2H, m), 0.16-0.12 (2H, m).

Example 114-(2-Cyclopropylethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamideExemplary Compound No. 1-62

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-cyclopropylethoxy)benzoyl]glycine (150 mg) prepared in Example 9(9b) and 4-(trifluoromethoxy)benzaldehyde (90 μL) to give thecorresponding oxazolone (176 mg). Then, the same reaction as in Example9 (9d) was conducted using 80 mg of this oxazolone to give 74 mg of thetitle compound (white powder).

mp: 142 to 144° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.75 (1H, brs), 8.04 (1H, t, J=6 Hz), 7.93 (2H, d, J=9 Hz), 7.62 (2H, d,J=9 Hz), 7.32 (2H, d, J=8 Hz), 7.14 (1H, brs), 7.02 (2H, d, J=9 Hz),4.62 (1H, t, J=5 Hz), 4.10 (2H, t, J=7 Hz), 3.43 (2H, q, J=6 Hz), 3.22(2H, q, J=6 Hz), 1.64 (2H, q, J=7 Hz), 0.89-0.79 (1H, m), 0.47-0.42 (2H,m), 0.16-0.12 (2H, m).

Example 124-(2-Cyclopropylethoxy)-N-((Z)-2-[4-(2,2-difluoroethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-64

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-cyclopropylethoxy)benzoyl]glycine (212 mg) prepared in Example 9(9b) and 4-(2,2-difluoroethoxy)benzaldehyde (170 mg) prepared in Example4 (4a) to give the corresponding oxazolone (281 mg). Then, the samereaction as in Example 9 (9d) was conducted using all this oxazolone togive 164 mg of the title compound (light yellow amorphous solid).

MS (FAB) m/z: 475 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.69 (1H, s), 7.98 (2H, d, J=9 Hz), 7.94 (1H, brt, J=5 Hz), 7.52 (2H, d,J=9 Hz), 7.20 (1H, s), 7.05 (2H, d, J=9 Hz), 6.98 (2H, d, J=9 Hz), 6.36(1H, tt, J=54 Hz, 3 Hz), 4.63 (1H, t, J=5 Hz), 4.31 (2H, td, J=14 Hz, 3Hz), 4.11 (2H, t, J=7 Hz), 3.44 (2H, q, J=6 Hz), 3.23 (2H, q, J=6 Hz),1.65 (2H, q, J=7 Hz), 0.89-0.81 (1H, m), 0.47-0.43 (2H, m), 0.16-0.12(2H, m).

Example 134-(2-Cyclopropylethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(2,2,2-trifluoroethoxy)phenyl]vinyl}benzamideExemplary Compound No. 1-65

(13a) 4-(2,2,2-Trifluoroethoxy)benzaldehyde

Sodium hydride (787 mg, 55%, 18.0 mmol) was suspended in DMF (10 mL)under a nitrogen atmosphere, and a solution of DMF (5 mL) containing4-hydroxybenzaldehyde (2.00 g, 16.4 mmol) was dropwise added theretoover 5 minutes at room temperature. A light yellow insoluble substancewas precipitated immediately after the addition. After 5 minutes, asolution of DMF (5 mL) containing 2,2,2-trifluoroethyl4-methylbenzenesulfonate (4.00 g, 17.2 mmol) was added dropwise theretoto give a brown solution. This brown solution was stirred at roomtemperature for 1 hour, and then water (100 mL) and ethyl acetate (150mL) were added thereto. The organic layer was separated, further washedwith water (50 mL) five times, with a 10% sodium hydroxide aqueoussolution (50 mL) three times, and with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated to give a crudeproduct. This crude product was purified by silica gel columnchromatography (hexane:ethyl acetate, 5:1, v/v) to give 1.40 g of thetitle compound (light yellow oil, yield: 42%).

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

9.94 (1H, s), 7.89 (2H, d, J=9 Hz), 7.07 (2H, d, J=9 Hz), 4.44 (2H, q,J=8 Hz).

(13b)4-(2-Cyclopropylethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(2,2,2-trifluoroethoxy)phenyl]vinyl}benzamide

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-cyclopropylethoxy)benzoyl]glycine (150 mg) prepared in Example 9(9b) and 4-(2,2,2-trifluoroethoxy)benzaldehyde (128 mg) prepared inExample 13 (13a) to give the corresponding oxazolone (215 mg). Then, thesame reaction as in Example 9 (9d) was conducted using 96 mg of thisoxazolone to give 65 mg of the title compound (white powder).

mp: 173 to 175° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.66 (1H, brs), 7.96-7.92 (3H, m), 7.51 (2H, d, J=9 Hz), 7.18 (1H, s),7.02 (2H, d, J=9 Hz), 7.00 (2H, d, J=9 Hz), 4.74 (2H, q, J=9 Hz), 4.62(1H, brt, J=5 Hz), 4.10 (2H, t, J=7 Hz), 3.42 (2H, q, J=6 Hz), 3.22 (2H,q, J=6 Hz), 1.64 (2H, q, J=7 Hz), 0.88-0.81 (1H, m), 0.47-0.43 (2H, m),0.16-0.12 (2H, m).

Example 14N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-cyclopropylethoxy)benzamideExemplary Compound No. 1-109

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-cyclopropylethoxy)benzoyl]glycine (213 mg) prepared in Example 9(9b) and 4-chlorobenzaldehyde (131 mg) to give the correspondingoxazolone (288 mg). Then, the same reaction as in Example 9 (9d) wasconducted using all this oxazolone to give 56 mg of the title compound(white powder).

mp: 143 to 145° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.75 (1H, s), 8.06 (1H, brt, J=5 Hz), 7.95 (2H, d, J=9 Hz), 7.54 (2H, d,J=9 Hz), 7.40 (2H, d, J=8 Hz), 7.14 (1H, s), 7.04 (2H, d, J=8 Hz), 4.64(1H, t, J=5 Hz), 4.11 (2H, t, J=6 Hz), 3.44 (2H, q, J=6 Hz), 3.23 (2H,q, J=6 Hz), 1.65 (2H, q, J=6 Hz), 0.88-0.81 (1H, m), 0.47-0.43 (2H, m),0.16-0.12 (2H, m).

Example 154-(2-Cyclopropylethoxy)-N-((Z)-2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-58

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-cyclopropylethoxy)benzoyl]glycine (210 mg) prepared in Example 9(9b) and 4-ethoxybenzaldehyde (122 μL) to give the correspondingoxazolone (180 mg). Then, the same reaction as in Example 9 (9d) wasconducted using all this oxazolone to give 154 mg of the title compound(white amorphous).

MS (FAB) m/z: 439 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.64 (1H, s), 7.95 (2H, d, J=9 Hz), 7.87 (1H, brt, J=5 Hz), 7.46 (2H, d,J=9 Hz), 7.17 (1H, s), 7.02 (2H, d, J=9 Hz), 6.85 (2H, d, J=9 Hz), 4.61(1H, t, J=6 Hz), 4.10 (2H, t, J=7 Hz), 3.99 (2H, q, J=7 Hz), 3.42 (2H,q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 1.65 (2H, q, J=7 Hz), 1.29 (3H, t, J=7Hz), 0.88-0.81 (1H, m), 0.47-0.43 (2H, m), 0.16-0.12 (2H, m).

Example 164-(2-Cyclopropylethoxy)-N-((Z)-2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-60

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-cyclopropylethoxy)benzoyl]glycine (263 mg) prepared in Example 9(9b) and 4-(cyclopropyloxy)benzaldehyde (170 mg) prepared in Example 6(6c) to give the corresponding oxazolone (235 mg). Then, the samereaction as in Example 9 (9d) was conducted using 156 mg of thisoxazolone to give 157 mg of the title compound (white powder).

mp: 132 to 134° C.;

¹H-nuclear magnetic resonance spectrum (500 MHz, CDCl₃) δ ppm:

7.88 (1H, brs), 7.82 (2H, d, J=9 Hz), 7.34 (2H, d, J=8 Hz), 7.06 (1H,s), 6.98 (2H, d, J=9 Hz), 6.93 (2H, d, J=8 Hz), 6.79 (1H, brt, J=6 Hz),4.08 (2H, t, J=6 Hz), 3.75 (2H, t, J=5 Hz), 3.70 (1H, sept, J=3 Hz),3.47 (2H, q, J=5 Hz), 1.71 (2H, q, J=6 Hz), 0.89-0.82 (1H, m), 0.78-0.73(4H, m), 0.52-0.49 (2H, m), 0.15-0.12 (2H, m).

Example 174-(2-Cyclopropylethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamideExemplary Compound No. 1-59

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-cyclopropylethoxy)benzoyl]glycine (211 mg) prepared in Example 9(9b) and 4-isopropoxybenzaldehyde (139 μL) to give the correspondingoxazolone (188 mg). Then, the same reaction as in Example 9 (9d) wasconducted using all this oxazolone to give 90.0 mg of the title compound(white amorphous).

MS (FAB) m/z: 453 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.67 (1H, brs), 7.98 (2H, d, J=9 Hz), 7.89 (1H, brt, J=5 Hz), 7.47 (2H,d, J=9 Hz), 7.18 (1H, s), 7.05 (2H d, J=9 Hz), 6.85 (2H, d, J=9 Hz),4.65-4.59 (2H, m), 4.11 (2H, t, J=7 Hz), 3.41 (2H, q, J=6 Hz), 3.22 (2H,q, J=6 Hz), 1.65 (2H, q, J=7 Hz), 1.23 (6H, d, J=6 Hz), 0.88-0.82 (1H,m), 0.47-0.43 (2H, m), 0.16-0.12 (2H, m).

Example 184-(2-Cyclopropylethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(1H-pyrrol-1-yl)phenyl]vinyl}benzamideExemplary Compound No. 1-72

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-cyclopropylethoxy)benzoyl]glycine (212 mg) prepared in Example 9(9b) and 4-(1H-pyrrol-1-yl)benzaldehyde (153 mg) to give thecorresponding oxazolone (328 mg). Then, the same reaction as in Example9 (9d) was conducted using all this oxazolone to give 113 mg of thetitle compound (white amorphous).

MS (FAB) m/z: 460 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.78 (1H, s), 8.03-7.98 (3H, m), 7.62 (2H, d, J=8 Hz), 7.58 (2H, d, J=9Hz), 7.42-7.41 (2H, m), 7.23 (1H, s), 7.06 (2H, d, J=8 Hz), 6.26-6.25(2H, m), 4.65 (1H, t, J=6 Hz), 4.12 (2H, t, J=6 Hz), 3.45 (2H, q, J=6Hz), 3.24 (2H, q, J=6 Hz), 1.65 (2H, q, J=6 Hz), 0.88-0.82 (1H, m),0.48-0.43 (2H, m), 0.16-0.14 (2H, m).

Example 194-(2-Cyclopropylethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamideExemplary Compound No. 1-69

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-cyclopropylethoxy)benzoyl]glycine (212 mg) prepared in Example 9(9b) and 4-(trifluoromethyl)benzaldehyde (122 μL) to give thecorresponding oxazolone (235 mg). Then, the same reaction as in Example9 (9d) was conducted using all this oxazolone to give 163 mg of thetitle compound (white powder).

mp: 174 to 176° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.80 (1H, s), 8.13 (1H, brt, J=6 Hz), 7.92 (2H, d, J=9 Hz), 7.69 (2H, d,J=9 Hz), 7.64 (2H, d, J=9 Hz), 7.14 (1H, s), 7.02 (2H, d, J=9 Hz), 4.63(1H, t, J=5 Hz), 4.10 (2H, t, J=7 Hz), 3.45 (2H, q, J=6 Hz), 3.23 (2H,q, J=6 Hz), 1.64 (2H, q, J=7 Hz), 0.87-0.81 (1H, m), 0.47-0.42 (2H, m),0.16-0.12 (2H, m).

Example 202-{[(2Z)-2-{[4-(2-Cyclopropylethoxy)benzoyl]amino}-3-(4-cyclopropylphenyl)propen-2-oyl]amino}ethylacetate Exemplary Compound No. 3-112

Acetyl chloride (97.0 μL, 1.36 mmol) and 1,4-diazabicyclo[2.2.2]octane(287 mg, 2.56 mmol) were added to a solution of dichloromethane (2 mL)containing4-(2-cyclopropylethoxy)-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide(197 mg, 0.453 mmol) prepared in Example 9 (9d). The mixture was stirredat room temperature for 14 hours, and then water was added thereto toterminate the reaction. The mixture was extracted with dichloromethane,and the organic layer was concentrated. The resulting residue waspurified by silica gel column chromatography (hexane:ethyl acetate, 1:3,v/v) to give 146 mg of the title compound (white powder, yield: 68%).

mp: 80 to 82° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.80 (2H, d, J=9 Hz), 7.65 (1H, brs), 7.28 (2H, d, J=8 Hz), 7.04 (1H,s), 6.99 (2H, d, J=8 Hz), 6.93 (2H, d, J=9 Hz), 6.73 (1H, brt, J=5 Hz),4.20 (2H, t, J=5 Hz), 4.08 (2H, t, J=7 Hz), 3.60 (2H, q, J=5 Hz), 2.03(3H, s), 1.89-1.82 (1H, m), 1.70 (2H, q, J=7 Hz), 1.00-0.96 (2H, m),0.90-0.84 (1H, m), 0.71-0.67 (2H, m), 0.53-0.48 (2H, m), 0.16-0.12 (2H,m).

Example 212-{[(2Z)-2-{[4-(2-Cyclopropylethoxy)benzoyl]amino}-3-(4-cyclopropylphenyl)propen-2-oyl]amino}ethylmorpholin-4-yl acetate Exemplary Compound No. 3-116

According to the method disclosed in the document (J. Med. Chem.,(1994), 37, 4538-4554), 73 mg of the title compound (white amorphous,yield: 16%) was synthesized using4-(2-cyclopropylethoxy)-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide(355 mg, 0.817 mmol) prepared in Example 9 (9d).

MS (ESI) m/z: 562 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.71 (1H, s), 8.13 (1H, brt, J=6 Hz), 7.97 (2H, d, J=9 Hz), 7.42 (2H, d,J=8H), 7.13 (1H, s), 7.05 (2H, d, J=8 Hz), 7.03 (2H, d, J=8 Hz),4.13-4.09 (4H, m), 3.56-3.54 (4H, m), 3.41-3.38 (2H, m), 3.19 (2H, s),2.48-2.47 (4H, m), 1.90-1.85 (1H, m), 1.65 (2H, q, J=6 Hz), 0.94-0.93(2H, m), 0.87-0.82 (1H, m), 0.68-0.65 (2H, m), 0.47-0.43 (2H, m),0.15-0.14 (2H, m).

Example 222-{[(2Z)-2-{[4-(2-Cyclopropylethoxy)benzoyl]amino}-3-(4-cyclopropylphenyl)propen-2-oyl]amino}ethylsuccinate Exemplary Compound No. 3-117

According to the method disclosed in the document (Tetrahedron Lett.,(1989), 30, 5045-5048), 198 mg of the title compound (white powder,yield: 88%) was synthesized using4-(2-cyclopropylethoxy)-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide(182 mg, 0.817 mmol) prepared in Example 9 (9d).

mp: 118° C. (dec.).

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

12.22 (1H, s), 9.71 (1H, s), 8.15 (1H, brt, J=6 Hz), 7.98 (2H, d, J=8Hz), 7.43 (2H, d, J=8 Hz), 7.14 (1H, s), 7.04 (2H, d, J=8 Hz), 7.02 (2H,d, J=8 Hz), 4.11 (2H, t, J=7 Hz), 4.06 (2H, t, J=6 Hz), 3.38 (2H, q, J=6Hz), 2.52-2.46 (4H, m), 1.90-1.85 (1H, m), 1.65 (2H, q, J=7 Hz),0.95-0.92 (2H, m), 0.89-0.81 (1H, m), 0.68-0.64 (2H, m), 0.47-0.43 (2H,m), 0.16-0.13 (2H, m).

Example 234-{2-[4-(Dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamideExemplary Compound No. 1-166

(23a) 4-{2-[4-(Dimethylamino)phenyl]ethoxy}benzoic acid

The same reaction as in Example 9 (9a) was conducted using2-[4-(dimethylamino)phenyl]ethanol (567 mg, 3.43 mmol) to give 567 mg ofthe title compound (powder, yield: 63%).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

12.56 (1H, brs), 7.84 (2H, d, J=9 Hz), 7.11 (2H, d, J=9 Hz), 6.98 (2H,d, J=9 Hz), 6.66 (2H, d, J=9 Hz), 4.16 (2H, t, J=7 Hz), 2.92 (2H, t, J=7Hz), 2.84 (6H, s).

(23b) N-(4-{2-[4-(Dimethylamino)phenyl]ethoxy}benzoyl)glycine

N-Ethyl-N,N-diisopropylamine (388 μL, 2.23 mmol) and4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (615mg, 2.22 mmol) were added to a solution of ethanol (10 mL) containing4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoic acid (567 mg, 1.99 mmol)prepared in Example 23 (23a) and glycine methyl ester hydrochloride (280mg, 2.23 mmol). The mixture was stirred at room temperature for 18hours, and a saturated sodium hydrogen carbonate aqueous solution wasadded thereto to terminate the reaction. The mixture was extracted withethyl acetate twice, and the organic layers were dried over anhydrousmagnesium sulfate. Then, the solvent was evaporated. The resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate, 1:1 to 2:5, v/v) to give an oily compound. To a solution ofethanol (6 mL) containing the resulting compound, a 2 M lithiumhydroxide aqueous solution (1.60 mL, 3.20 mmol) was added. The mixturewas stirred at 60° C. for 40 minutes, and then 10% hydrochloric acid(3.5 mL) was added thereto under ice-cooling. The mixture was extractedwith ethyl acetate, and the organic layers were combined, washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated to give 395 mg of the title compound (white powder,yield: 58%)

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

12.50 (1H, brs), 8.65 (1H, brt, J=6 Hz), 7.80 (2H, d, J=9 Hz), 7.11 (2H,d, J=9 Hz), 6.98 (2H, d, J=9 Hz), 6.66 (2H, d, J=9 Hz), 4.15 (2H, t, J=7Hz), 3.87 (2H, d, J=6 Hz), 2.92 (2H, t, J=7 Hz), 2.84 (6H, s).

(23c)(4Z)-2-(4-{2-[4-(Dimethylamino)phenyl]ethoxy}phenyl)-4-[4-(trifluoromethoxy)benzylidene]-1,3-oxazol-5(4H)-one

A mixture of N-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine(241 mg, 0.676 mmol) prepared in Example 23 (23b),4-(trifluoromethoxy)benzaldehyde (106 μL, 0.742 mmol), sodium acetate(83.9 mg, 1.02 mmol), and acetic anhydride (319 μL, 3.38 mmol) wasstirred at 120° C. for 15 minutes and then allowed to cool to roomtemperature. A saturated sodium hydrogen carbonate aqueous solution,hexane, and ethanol were added to the resulting solidified product whichwas washed by ultrasonic vibration. The precipitate was collected byfiltration and dried by heating under reduced pressure to give 234 mg ofthe title compound (orange solid, yield: 70%).

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.25 (2H, d, J=9 Hz), 8.11 (2H, d, J=9 Hz), 7.31 (2H, d, J=9 Hz), 7.18(2H, d, J=8 Hz), 7.13 (1H, s), 7.02 (2H, d, J=9 Hz), 6.73 (2H, d, J=8Hz), 4.22 (2H, t, J=7 Hz), 3.05 (2H, t, J=7 Hz), 2.94 (6H, s).

(23d)4-{2-[4-(Dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide

2-Aminoethanol (57 μL, 0.944 mmol) was added to a solution of ethanol(0.5 mL) containing(4Z)-2-(4-{2-[4-(dimethylamino)phenyl]ethoxy}phenyl)-4-[4-(trifluoromethoxy)benzylidene]-1,3-oxazol-5(4H)-one(234 mg, 0.471 mmol) prepared in Example 23 (23c). The mixture wasstirred at 60° C. for 2.5 hours, and then the solvent was evaporated.The resulting residue was purified by silica gel column chromatography(ethyl acetate:methanol, 50:1, v/v) to give 167 mg of the title compound(white amorphous solid, yield: 64%).

MS (FAB) m/z: 558 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.79 (1H, s), 8.07 (1H, brt, J=5 Hz), 7.95 (2H, d, J=9 Hz), 7.64 (2H, d,J=9 Hz), 7.34 (2H, d, J=8 Hz), 7.16 (1H, s), 7.14 (2H, d, J=8 Hz), 7.04(2H, d, J=9 Hz), 6.69 (2H, d, J=9 Hz), 4.64 (1H, t, J=5 Hz), 4.19 (2H,q, J=7 Hz), 3.45 (2H, q, J=6 Hz), 3.23 (2H, q, J=6 Hz), 2.94 (2H, t, J=7Hz), 2.85 (6H, s).

Example 24N-((Z)-2-[4-(Difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamideExemplary Compound No. 1-65

The same reaction as in Example 23 (23c) was conducted usingN-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (230 mg)prepared in Example 23 (23b) and 4-(difluoromethoxy)benzaldehyde (93.8μL) to give the corresponding oxazolone (387 mg). Then, the samereaction as in Example 23 (23d) was conducted using all this oxazoloneto give 247 mg of the title compound (white amorphous solid).

MS (FAB) m/z: 540 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.73 (1H, s), 8.02 (1H, brt, J=5 Hz), 7.95 (2H, d, J=9 Hz), 7.58 (2H, d,J=9 Hz), 7.25 (1H, t, J=74 Hz), 7.18 (1H, s), 7.14 (2H, d, J=8 Hz), 7.13(2H, d, J=9 Hz), 7.04 (2H, d, J=9 Hz), 6.69 (2H, d, J=9 Hz), 4.63 (1H,t, J=5 Hz), 4.19 (2H, t, J=7 Hz), 3.44 (2H, q, J=6 Hz), 3.23 (2H, q, J=6Hz), 2.94 (2H, t, J=7 Hz), 2.85 (6H, s).

Example 25N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamideExemplary Compound No. 1-172

The same reaction as in Example 23 (23c) was conducted usingN-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (324 mg)prepared in Example 23 (23b) and 4-cyclopropylbenzaldehyde (170 mg)prepared in Example 5 to give the corresponding oxazolone (360 mg).Then, the same reaction as in Example 23 (23d) was conducted using allthis oxazolone to give 293 mg of the title compound (white amorphoussolid).

MS (FAB) m/z: 514 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.69 (1H, s), 7.97-7.93 (3H, m), 7.41 (2H, d, J=7 Hz), 7.17 (1H, s),7.15 (2H, d, J=8 Hz), 7.04 (2H, d, J=8 Hz), 7.02 (2H, d, J=8 Hz), 6.69(2H, d, J=7 Hz), 4.63 (1H, t, J=5 Hz), 4.20 (2H, t, J=7 Hz), 3.43 (2H,q, J=6 Hz), 3.22 (2H, q, J=6 Hz), 2.94 (2H, t, J=7 Hz), 2.86 (6H, s),1.90-1.84 (1H, m), 0.95-0.91 (2H, m), 0.67-0.64 (2H, m).

Example 26N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamidehydrochloride Exemplary Compound No. 1-172

A mixture solution of a 4 N hydrochloric acid ethyl acetate solution (97μL, 0.388 mmol) and methanol (680 μL) was added to a solution ofmethanol (3 mL) containingN-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[4-(dimethylamino)phenyl]ethoxy}benzamide(133 mg, 0.259 mmol) prepared in Example 25. The resulting mixture wasstirred at room temperature for 45 minutes. The reaction mixture wasconcentrated and dried to give 150 mg of the title compound (whiteamorphous solid).

Elemental analysis (%), as C₃₁H₃₅N₃O₄.HCl.3/2H₂O: Theoretical value: C,64.52; H, 6.81; N, 7.28; Cl, 6.14, Measured value: C, 64.47; H, 6.86; N,6.82; Cl, 5.75.

Example 274-{2-[4-(Dimethylamino)phenyl]ethoxy}-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamideExemplary Compound No. 1-163

The same reaction as in Example 23 (23c) was conducted usingN-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (255 mg)prepared in Example 23 (23b) and 4-(isopropoxy)benzaldehyde (174 mg) togive the corresponding oxazolone (189 mg). Then, the same reaction as inExample 23 (23d) was conducted using 185 mg of this oxazolone to give 89mg of the title compound (white amorphous solid).

MS (FAB) m/z: 532 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.63 (1H, brs), 7.94 (2H, d, J=9 Hz), 7.86 (1H, brt, J=5 Hz), 7.44 (2H,d, J=9 Hz), 7.16 (1H, s), 7.12 (2H, d, J=9 Hz), 7.02 (2H, d, J=9 Hz),6.84 (2H, d, J=9 Hz), 6.67 (2H, d, J=9 Hz), 4.63-4.57 (2H, m), 4.18 (2H,t, J=7 Hz), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 2.93 (2H, t, J=7Hz), 2.85 (6H, s), 1.22 (6H, d, J=6 Hz).

Example 284-{2-[4-(Dimethylamino)phenyl]ethoxy}-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamidehydrochloride Exemplary Compound No. 1-163

A mixture solution of a 4 N hydrochloric acid ethyl acetate solution (27μL, 0.108 mmol) and methanol (186 μL) was added to a solution ofmethanol (1 mL) containing4-{2-[4-(dimethylamino)phenyl]ethoxy}-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide(37.7 mg, 0.071 mmol) prepared in Example 27. The resulting mixture wasstirred at room temperature for 40 minutes. The reaction mixture wasconcentrated and dried to give 42.3 mg of the title compound (whitepowder, yield: 99%).

mp: 103 to 105° C.;

Elemental analysis (%), as C₃₁H₃₇N₃O₅.HCl.2H₂O: Theoretical value: C,61.63; H, 7.01; N, 6.96; Cl, 5.87, Measured value: C, 61.62; H, 6.74; N,6.93; Cl, 5.67.

Example 294-{2-[4-(Dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamideExemplary Compound No. 1-173

The same reaction as in Example 23 (23c) was conducted usingN-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (202 mg)prepared in Example 23 (23b) and 4-(trifluoromethyl)benzaldehyde (90.6μL) to give the corresponding oxazolone (241 mg). Then, the samereaction as in Example 23 (23d) was conducted using all this oxazoloneto give 165 mg of the title compound (white amorphous solid).

MS (FAB) m/z: 542 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.84 (1H, s), 8.16 (1H, brt, J=6 Hz), 7.93 (2H, d, J=8 Hz), 7.70 (4H,s), 7.16 (1H, s), 7.14 (2H, d, J=8 Hz), 7.04 (2H, d, J=8 Hz), 6.69 (2H,d, J=8 Hz), 4.65 (1H, t, J=5 Hz), 4.19 (2H, t, J=7 Hz), 3.45 (2H, q, J=6Hz), 3.23 (2H, q, J=6 Hz), 2.94 (2H, t, J=7 Hz), 2.85 (6H, s).

Example 30N-((Z)-2-[4-(Difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxybenzamideExemplary Compound No. 1-4

(30a) N-(4-Isobutoxybenzoyl)glycine

The same reaction as in Example 9 (9b) was conducted using4-isobutoxybenzoic acid (55.0 g, 283 mmol) prepared according to themethod disclosed in the document (J. Am. Chem. Soc., 61, 3050 (1939)) togive 50.2 g of the title compound (colorless crystalline solid, yield:71%).

mp: 140 to 142° C.

(30b)N-((Z)-2-[4-(Difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxybenzamide

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (184 mg) prepared in Example 30 (30a) and4-(difluoromethoxy)benzaldehyde (165 mg) to give 195 mg of thecorresponding oxazolone. Then, the same reaction as in Example 9 (9d)was conducted using all this oxazolone to give 99 mg of the titlecompound (white powder).

mp: 75 to 78° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.17 (1H, brs), 7.78 (2H, d, J=9 Hz), 7.35 (2H, d, J=9 Hz), 7.02 (2H, d,J=9 Hz), 6.97 (1H, brt, J=5 Hz), 6.94 (1H, s), 6.89 (2H, d, J=9 Hz),6.47 (1H, t, J=74 Hz), 3.75 (2H, d, J=7 Hz), 3.73-3.72 (2H, m), 3.44(2H, q, J=5 Hz), 3.26 (1H, brs), 2.10 (1H, sept, J=7 Hz), 1.04 (6H, d,J=7 Hz).

Example 31N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-isobutoxybenzamideExemplary Compound No. 1-5

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (539 mg) prepared in Example 30 (30a) and4-(trifluoromethoxy)benzaldehyde (351 μL) to give the correspondingoxazolone (659 mg). Then, the same reaction as in Example 9 (9d) wasconducted using 106 mg of this oxazolone to give 58 mg of the titlecompound (white powder).

mp: 170 to 171° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.76 (3H, brd, J=9 Hz), 7.39 (2H, d, J=9 Hz), 7.15 (2H, d, J=8 Hz), 7.01(1H, s), 6.91 (2H, d, J=9 Hz), 6.68 (1H, brt, J=6 Hz), 3.78 (2H, brs),3.76 (2H, d, J=7 Hz), 3.51 (2H, q, J=5 Hz), 2.97 (1H, brs), 2.11 (1H,sept, J=7 Hz), 1.04 (6H, d, J=7 Hz).

Example 32N-((Z)-2-[4-(2,2-Difluoroethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxybenzamideExemplary Compound No. 1-7

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (184 mg) prepared in Example 30 (30a) and4-(2,2-difluoroethoxy)benzaldehyde (150 mg) prepared in Example 4 (4a)to give the corresponding oxazolone (256 mg). Then, the same reaction asin Example 9 (9d) was conducted using 122 mg of this oxazolone to give63 mg of the title compound (white powder).

mp: 150 to 151° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.66 (1H, brs), 7.97-7.90 (3H, m), 7.49 (2H, d, J=9 Hz), 7.18 (1H, s),7.02 (2H, d, J=9 Hz), 6.95 (2H, d, J=9 Hz), 6.34 (1H, tt, J=54 Hz, 4Hz), 4.62 (1H, brt, J=5 Hz), 4.29 (2H, td, J=15 Hz, 3 Hz), 3.83 (2H, d,J=6 Hz), 3.43 (2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 2.04 (1H, sept, J=7Hz), 1.00 (6H, d, J=7 Hz).

Example 33N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(2,2,2-trifluoroethoxy)phenyl]vinyl}-4-isobutoxybenzamideExemplary Compound No. 1-8

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (500 mg) prepared in Example 30 (30a) and4-(2,2,2-trifluoroethoxy)benzaldehyde (447 mg) prepared in Example 13(13a) to give the corresponding oxazolone (592 mg). Then, the samereaction as in Example 9 (9d) was conducted using 100 mg of thisoxazolone to give 85 mg of the title compound (white solid).

mp: 176 to 178° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 7.80 (2H,d, J=9 Hz), 7.70 (1H, brs), 7.38 (2H, d, J=9 Hz), 7.08 (1H, s), 6.94(2H, d, J=9 Hz), 6.90 (2H, d, J=9 Hz), 6.66 (1H, brs), 4.33 (2H, q, J=8Hz), 3.80-3.76 (4H, m), 3.52 (2H, q, J=5 Hz), 2.10 (1H, sept, J=7 Hz),1.05 (6H, d J=7 Hz).

Example 34N-((Z)-2-(4-Ethylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxybenzamideExemplary Compound No. 1-10

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (520 mg) prepared in Example 30 (30a) and4-ethylbenzaldehyde (312 μL) to give the corresponding oxazolone (442mg). The same reaction as in Example 9 (9d) was conducted using 122 mgof this oxazolone to give 110 mg of the title compound (white powder).

mp: 174 to 176° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.81 (2H, d, J=9 Hz), 7.61 (1H, brs), 7.33 (2H, d, J=8 Hz), 7.19 (2H, d,J=8 Hz), 7.10 (1H, s), 6.95 (2H, d, J=9 Hz), 6.56 (1H, t, J=6 Hz),3.83-3.80 (2H, m), 3.78 (2H, d, J=7 Hz), 3.53 (2H, q, J=5 Hz), 2.64 (2H,q, J=7 Hz), 2.11 (1H, quint, J=7 Hz), 1.23 (3H, t, J=7 Hz), 1.04 (6H, d,J=7 Hz).

Example 35N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropylphenyl)vinyl]-4-isobutoxybenzamideExemplary Compound No. 1-11

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (183 mg) prepared in Example 30 (30a) and4-isopropylbenzaldehyde (118 mg) to give the corresponding oxazolone(188 mg). Then, the same reaction as in Example 9 (9d) was conductedusing all this oxazolone to give 127 mg of the title compound (whitepowder).

mp: 178 to 180° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.06 (1H, brs), 7.80 (2H, d, J=9 Hz), 7.31 (2H, d, J=8 Hz), 7.16 (2H, d,J=8 Hz), 7.00 (1H, s), 6.90-6.88 (3H, m), 3.75 (2H, d, J=6 Hz), 3.71(2H, q, J=5 Hz), 3.43-3.40 (3H, m), 2.86 (1H, sept, J=7 Hz), 2.10 (1H,sept, J=7 Hz), 1.22 (6H, d, J=7 Hz), 1.04 (6H, d, J=7 Hz).

Example 36N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxybenzamideExemplary Compound No. 1-12

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (215 mg) prepared in Example 30 (30a) and4-cyclopropylbenzaldehyde (135 mg) prepared in Example 5 to give thecorresponding oxazolone (215 mg). Then, the same reaction as in Example9 (9d) was conducted using all this oxazolone to give 126 mg of thetitle compound (white powder).

mp: 180 to 181° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.69 (1H, brs), 7.96 (2H, d, J=9 Hz), 7.94 (1H, brt, J=6 Hz), 7.42 (2H,d, J=8 Hz), 7.17 (1H, s), 7.04 (2H, d, J=9 Hz), 7.02 (2H, d, J=8 Hz),4.62 (1H, t, J=5 Hz), 3.84 (2H, d, J=6 Hz), 3.43 (2H, q, J=6 Hz), 3.22(2H, q, J=6 Hz), 2.05 (1H, sept, J=7 Hz), 1.90-1.85 (1H, m), 1.00 (6H,d, J=7 Hz), 0.95-0.91 (2H, m), 0.67-0.64 (2H, m).

Example 37N-((Z)-2-(4-Cyclopent-1-en-1-ylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxybenzamideExemplary Compound No. 1-14

(37a)-4-Cyclopent-1-en-1-ylbenzaldehyde

n-Butyllithium (7.2 mL, 1.56 M hexane solution, 11.2 mmol) was added toa solution in THF (25 mL) of 1-bromo-4-(dimethoxymethyl)benzene (2.29 g,9.91 mmol) at −78° C. The mixture was stirred at the same temperaturefor 2 hours, and then cyclopentanone (1.34 mL, 15.1 mmol) was addedthereto. The resulting mixture was heated to room temperature and thenstirred for 1 hour. The reaction was terminated by adding a saturatedammonium chloride aqueous solution, and an extraction with ethyl acetatewas conducted three times. The resulting organic layers were washed withwater and saturated brine and then dried over anhydrous magnesiumsulfate. The solvent was evaporated, and the resulting residue waspurified by silica gel column chromatography (hexane:ethyl acetate, 5:1,v/v) to give an oily compound. Trifluoroacetic acid (9 mL) was added toa dichloromethane-water (9.1 mL, 100:1, v/v) mixture solution containingthe resulting oily compound at room temperature, and the mixture wascontinuously stirred for 20 minutes. The solvent was evaporated, and theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate, 10:1, v/v) to give 1.18 g of the title compound(light brown crystalline solid, yield: 90%).

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

9.97 (1H, s), 7.83 (2H, d, J=8 Hz), 7.58 (2H, d, J=8 Hz), 6.41-6.40 (1H,m), 2.77-2.73 (2H, m), 2.60-2.56 (2H, m), 2.06 (2H, quint, J=7 Hz).

(37b)N-((Z)-2-(4-Cyclopent-1-en-1-ylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxybenzamide

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (216 mg) prepared in Example 30 (30a) and4-cyclopent-1-en-1-ylbenzaldehyde (157 mg) prepared in Example 37 (37a)to give the corresponding oxazolone (194 mg). Then, the same reaction asin Example 9 (9d) was conducted using all this oxazolone to give 128 mgof the title compound (white amorphous solid).

MS (FAB) m/z: 449 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.72 (1H, s), 7.98-7.94 (3H, m), 7.48 (2H, d, J=8 Hz), 7.39 (2H, d, J=8Hz), 7.16 (1H, s), 7.02 (2H, d, J=8 Hz), 6.31 (1H, brs), 4.62 (1H, brt,J=5 Hz), 3.82 (2H, d, J=6 Hz), 3.43 (2H, q, J=6 Hz), 3.22 (2H, q, J=6Hz), 2.63-2.59 (2H, m), 2.47-2.44 (2H, m), 2.04 (1H, sept, J=6 Hz), 1.92(2H, quint, J=7 Hz), 0.99 (6H, d, J=6 Hz).

Example 38N-((Z)-2-(4-Ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxybenzamideExemplary Compound No. 1-1

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (514 mg) prepared in Example 30 (30a) and4-ethoxybenzaldehyde (338 mg) to give the corresponding oxazolone (422mg). Then, the same reaction as in Example 9 (9d) was conducted using102 mg of this oxazolone to give 54 mg of the title compound (whitepowder).

mp: 124 to 125° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.64 (1H, brs), 7.95 (2H, d, J=9 Hz), 7.86 (1H, brt, J=5 Hz), 7.46 (2H,d, J=9 Hz), 7.17 (1H, s), 7.02 (2H, d, J=9 Hz), 6.85 (2H, d, J=9 Hz),4.61 (1H, brt, J=6 Hz), 4.00 (2H, q, J=7 Hz), 3.83 (2H, q, J=7 Hz), 3.42(2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 2.04 (1H, sept, J=6 Hz), 1.29(3H, t, J=7 Hz), 1.00 (6H, d, J=7 Hz).

Example 39N-((Z)-2-[4-(Cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxybenzamideExemplary Compound No. 1-3

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (155 mg) prepared in Example 30 (30a) and4-(cyclopropyloxy)benzaldehyde (200 mg) prepared in Example 6 (6c) togive the corresponding oxazolone (141 mg). Then, the same reaction as inExample 9 (9d) was conducted using 126 mg of this oxazolone to give 126mg of the title compound (white amorphous solid).

MS (FAB) m/z: 439 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.03 (1H, brs), 7.79 (2H, d, J=9 Hz), 7.29 (2H, d, J=9 Hz), 6.99 (1H,s), 6.93 (2H, d, J=9 Hz), 6.89 (1H, t, J=6 Hz), 6.87 (2H, t, J=9 Hz),3.74 (2H, d, J=6 Hz), 3.71-3.67 (3H, m), 3.42 (2H, q, J=5 Hz), 3.38 (1H,brs), 2.09 (1H, sept, J=7 Hz), 1.04 (6H, d, J=7 Hz), 0.80-0.71 (4H, m).

Example 40N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]vinyl}-4-isobutoxybenzamideExemplary Compound No. 1-9

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (518 mg) prepared in Example 30 (30a) and4-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (375 μL) to give thecorresponding oxazolone (715 mg). Then, the same reaction as in Example9 (9d) was conducted using 101 mg of this oxazolone to give 89 mg of thetitle compound (white solid).

mp: 174 to 177° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.79 (2H, d, J=9 Hz), 7.66 (1H, brs), 7.42 (2H, d, J=9 Hz), 7.19 (2H, d,J=8 Hz), 7.07 (1H, s), 6.95 (2H, d, J=9 Hz), 6.62 (1H, brt, J=6 Hz),5.90 (1H, tt, J=53 Hz, 3 Hz), 3.83-3.79 (2H, m), 3.78 (2H, d, J=6 Hz),3.53 (2H, q, J=5 Hz), 2.91 (1H, brs), 2.11 (1H, quint, J=7 Hz), 1.04(6H, d, J=7 Hz).

Example 41N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(methylthio)phenyl]vinyl}-4-isobutoxybenzamideExemplary Compound No. 1-15

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (520 mg) prepared in Example 30 (30a) and4-(methylthio)benzaldehyde (303 μL) to give the corresponding oxazolone(594 mg). Then, the same reaction as in Example 9 (9d) was conductedusing 129 mg of this oxazolone to give 134 mg of the title compound(white powder).

mp: 161 to 163° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.30 (1H, brs), 7.78 (2H, d, J=9 Hz), 7.24 (2H, d, J=9 Hz), 7.09 (2H, d,J=9 Hz), 7.08 (1H, brt, J=5 Hz), 6.88 (1H, s), 6.87 (2H, d, J=9 Hz),3.74 (2H, d, J=7 Hz), 3.67 (2H, brs), 3.46 (1H, brs), 3.39 (2H, q, J=5Hz), 2.43 (3H, s), 2.10 (1H, sept, J=7 Hz), 1.04 (6H, d, J=7 Hz).

Example 42N-((Z)-2-[4-(Ethylthio)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-isobutoxybenzamideExemplary Compound No. 1-16

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (520 mg) prepared in Example 30 (30a) and4-(ethylthio)benzaldehyde (387 mg) to give the corresponding oxazolone(574 mg). Then, the same reaction as in Example 9 (9d) was conductedusing 100 mg of this oxazolone to give 82 mg of the title compound(white powder).

mp: 153 to 155° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.80 (2H, d, J=9 Hz), 7.70 (1H, brs), 7.31 (2H, d, J=8 Hz), 7.23 (2H, d,J=9 Hz), 7.05 (1H, brs), 6.94 (2H, d, J=9 Hz), 6.65 (1H, brs), 3.81-3.76(4H, m), 3.51 (2H, q, J=5 Hz), 3.05 (1H, brs), 2.95 (2H, q, J=7 Hz),2.16-2.04 (1H, m), 1.33 (3H, t, J=7 Hz), 1.04 (6H, d, J=7 Hz).

Example 43N-((Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-{4-[(trifluoromethyl)thio]phenyl}vinyl)-4-isobutoxybenzamideExemplary Compound No. 1-17

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (512 mg) prepared in Example 30 (30a) and4-[(trifluoromethyl)thio]benzaldehyde (462 mg) to give the correspondingoxazolone (719 mg). Then, the same reaction as in Example 9 (9d) wasconducted using 101 mg of this oxazolone to give 101 mg of the titlecompound (light yellow amorphous solid).

MS (FAB) m/z: 483 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 8.39 (1H,brs), 7.76 (2H, d, J=9 Hz), 7.53 (2H, d, J=8 Hz), 7.35 (2H, d, J=8 Hz),7.07 (1H, brt, J=5 Hz), 6.87 (2H, d, J=9 Hz), 6.85 (1H, s), 3.75 (2H, d,J=7 Hz), 3.70 (2H, q, J=4 Hz), 3.40 (2H, q, J=5 Hz), 3.28 (1H, brt, J=5Hz), 2.10 (1H, sept, J=7 Hz), 1.04 (6H, d, J=7 Hz).

Example 44N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(1H-pyrrol-1-yl)phenyl]vinyl}-4-isobutoxybenzamideExemplary Compound No. 1-18

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (520 mg) prepared in Example 30 (30a) and4-(1H-pyrrol-1-yl)benzaldehyde (390 mg) to give the correspondingoxazolone (723 mg). Then, the same reaction as in Example 9 (9d) wasconducted using 200 mg of this oxazolone to give 163 mg of the titlecompound (white powder).

mp: 174 to 176° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.18 (1H, brs), 7.76 (2H, d, J=9 Hz), 7.38 (2H, d, J=9 Hz), 7.26 (2H, d,J=9 Hz), 7.02 (2H, t, J=2 Hz), 6.99 (1H, brt, J=6 Hz), 6.96 (1H, brs),6.84 (2H, d, J=9 Hz), 6.31 (2H, t, J=2 Hz), 3.74-3.69 (4H, m), 3.44 (2H,q, J=4 Hz), 2.08 (1H, sept, J=7 Hz), 1.03 (6H, d, J=7 Hz).

Example 45N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-isobutoxybenzamideExemplary Compound No. 1-13

The same reaction as in Example 9 (9c) was conducted usingN-(4-isobutoxybenzoyl)glycine (524 mg) prepared in Example 30 (30a) and4-(trifluoromethyl)benzaldehyde (314 μL) to give the correspondingoxazolone (663 mg). Then, the same reaction as in Example 9 (9d) wasconducted using 95 mg of this oxazolone to give 43 mg of the titlecompound (colorless crystalline solid).

mp: 207 to 210° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.82 (1H, brs), 7.74 (2H, d, J=9 Hz), 7.56 (2H, d, J=8 Hz), 7.46 (2H, d,J=8 Hz), 7.00 (1H, s), 6.91 (2H, d, J=9 Hz), 6.68 (1H, brt, J=6 Hz),3.80 (2H, brs), 3.76 (2H, d, J=7 Hz), 3.52 (2H, q, J=5 Hz), 2.92 (1H,brs), 2.10 (1H, sept, J=7 Hz), 1.04 (6H, d, J=7 Hz).

Example 464-(Cyclobutylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamideExemplary Compound No. 1-251

(46a) N-[4-(Cyclobutylmethoxy)benzoyl]glycine

The same reactions as in Example 9 (9a) and (9b) were conducted usingmethyl 4-hydroxybenzoate (3.81 g, 25.0 mmol) and cyclobutylmethanol(2.36 mL, 25.0 mmol) to give 6.41 g of the title compound (colorlessoil, yield: 97%).

(46b)4-(Cyclobutylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide

The same reaction as in Example 9 (9c) was conducted usingN-[4-(cyclobutylmethoxy)benzoyl]glycine (150 mg) prepared in Example 46(46a) and 4-(trifluoromethoxy)benzaldehyde (90 μL) to give thecorresponding oxazolone (161 mg). Then, the same reaction as in Example9 (9d) was conducted using 81 mg of this oxazolone to give 73 mg of thetitle compound (white powder).

mp: 168 to 170° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.75 (1H, brs), 8.04 (1H, t, J=6 Hz), 7.92 (2H, d, J=9 Hz), 7.62 (2H, d,J=9H), 7.32 (2H, d, J=8 Hz), 7.14 (1H, brs), 7.02 (2H, d, J=9 Hz), 4.62(1H, brt, J=6 Hz), 4.02 (2H, d, J=7 Hz), 3.43 (2H, q, J=6 Hz), 3.22 (2H,q, J=6 Hz), 2.73 (1H, sept, J=7 Hz), 2.12-2.04 (2H, m), 1.96-1.79 (4H,m).

Example 47N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenylethoxy)benzamideExemplary Compound No. 1-112

(47a) N-[4-(2-Phenylethoxy)benzoyl]glycine

The same reactions as in Example 9 (9a) and (9b) were conducted usingmethyl 4-hydroxybenzoate (2.23 g, 14.7 mmol) and 2-phenylethanol (1.80mL, 15.1 mmol) to give 3.23 g of the title compound (light yellowpowder, yield: 74%).

[In this case, a 2 N sodium hydroxide aqueous solution was used insteadof a 2 M lithium hydroxide aqueous solution.]

(47b)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenylethoxy)benzamide

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-phenylethoxy)benzoyl]glycine (174 mg) prepared in Example 47(47a) and 4-isopropoxybenzaldehyde (101 μL) to give the correspondingoxazolone (205 mg). Then, the same reaction as in Example 9 (9d) wasconducted using all this oxazolone to give 111 mg of the title compound(white amorphous solid).

MS (FAB) m/z: 488 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.64 (1H, brs), 7.95 (2H, d, J=9 Hz), 7.86 (1H, brt, J=6 Hz), 7.45 (2H,d, J=9 Hz), 7.34-7.28 (4H, m), 7.23-7.20 (1H, m), 7.16 (1H, s), 7.03(2H, d, J=9 Hz), 6.84 (2H, d, J=9 Hz), 4.63-4.57 (2H, m), 4.28 (2H, t,J=7 Hz), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 3.06 (2H, t, J=7Hz), 1.22 (6H, d, J=7 Hz).

Example 48N-((Z)-2-[4-(Difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-phenylethoxy)benzamideExemplary Compound No. 1-114

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-phenylethoxy)benzoyl]glycine (150 mg) prepared in Example 47(47a) and 4-(difluoromethoxy)benzaldehyde (73 μL) to give thecorresponding oxazolone (181 mg). Then, the same reaction as in Example9 (9d) was conducted using 88 mg of this oxazolone to give 74 mg of thetitle compound (white powder).

mp: 155 to 157° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.71 (1H, brs), 8.00 (1H, brt, J=6 Hz), 7.93 (2H, d, J=9 Hz), 7.56 (2H,d, J=9 Hz), 7.33-7.28 (4H, m), 7.23 (1H, t, J=74 Hz), 7.22-7.19 (1H, m),7.16 (1H, s), 7.11 (2H, d, J=9 Hz), 7.03 (2H, d, J=9 Hz), 4.62 (1H, brt,J=5 Hz), 4.27 (2H, t, J=7 Hz), 3.42 (2H, q, J=6 Hz), 3.22 (2H, q, J=6Hz), 3.06 (2H, t, J=7 Hz).

Example 49N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(2-phenylethoxy)benzamideExemplary Compound No. 1-115

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-phenylethoxy)benzoyl]glycine (150 mg) prepared in Example 47(47a) and 4-(trifluoromethoxy)benzaldehyde (79 μL) to give thecorresponding oxazolone (172 mg). Then, the same reaction as in Example9 (9d) was conducted using 80 mg of this oxazolone to give 64 mg of thetitle compound (white amorphous solid).

MS (FAB) m/z: 515 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.76 (1H, brs), 8.04 (1H, brt, J=6 Hz), 7.92 (2H, d, J=9 Hz), 7.61 (2H,d, J=9 Hz), 7.34-7.28 (6H, m), 7.23-7.20 (1H, m), 7.14 (1H, s), 7.03(2H, d, J=9 Hz), 4.62 (1H, brt, J=5 Hz), 4.27 (2H, t, J=7 Hz), 3.43 (2H,q, J=6 Hz), 3.22 (2H, q, J=6 Hz), 3.06 (2H, t, J=7 Hz).

Example 50N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(2,2,2-trifluoroethoxy)phenyl]vinyl}-4-(2-phenylethoxy)benzamideExemplary Compound No. 1-118

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-phenylethoxy)benzoyl]glycine (150 mg) prepared in Example 47(47a) and 4-(2,2,2-trifluoroethoxy)benzaldehyde (113 mg) prepared inExample 13 (13a) to give the corresponding oxazolone (186 mg). Then, thesame reaction as in Example 9 (9d) was conducted using 88 mg of thisoxazolone to give 64 mg of the title compound (white solid).

mp: 194 to 196° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.68 (1H, brs), 7.95-7.92 (3H, m), 7.50 (2H, d, J=9 Hz), 7.34-7.28 (4H,m), 7.24-7.19 (2H, m), 7.03 (2H, d, J=9 Hz), 6.99 (2H, d, J=9 Hz), 4.74(2H, q, J=9 Hz), 4.62 (1H, brt, J=5 Hz), 4.27 (2H, t, J=7 Hz), 3.42 (2H,q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 3.06 (2H, t, J=7 Hz).

Example 51N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-phenylethoxy)benzamideExemplary Compound No. 1-121

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-phenylethoxy)benzoyl]glycine (180 mg) prepared in Example 47(47a) and 4-cyclopropylbenzaldehyde (97 mg) prepared in Example 5 togive the corresponding oxazolone (196 mg). Then, the same reaction as inExample 9 (9d) was conducted using 95 mg of this oxazolone to give 67 mgof the title compound (light yellow powder).

mp: 113 to 115° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm: 9.66(1H, brs), 7.94 (2H, d, J=9 Hz), 7.92 (1H, t, J=6 Hz), 7.39 (2H, d, J=8Hz), 7.34-7.28 (4H, m), 7.24-7.20 (1H, m), 7.14 (1H, brs), 7.03 (2H, d,J=9 Hz), 7.00 (2H, d, J=9 Hz), 4.61 (1H, t, J=6 Hz), 4.28 (2H, t, J=7Hz), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 3.06 (2H, t, J=7 Hz),1.90-1.83 (1H, m), 0.95-0.90 (2H, m), 0.67-0.63 (2H, m).

Example 52N-((Z)-2-[4-(Cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-phenylethoxy)benzamideExemplary Compound No. 1-113

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-phenylethoxy)benzoyl]glycine (185 mg) prepared in Example 47(47a) and 4-(cyclopropyloxy)benzaldehyde (180 mg) prepared in Example 6(6c) to give the corresponding oxazolone (220 mg). Then, the samereaction as in Example 9 (9d) was conducted using 101 mg of thisoxazolone to give 58 mg of the title compound (light yellow amorphoussolid).

MS (FAB) m/z: 487 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.65 (1H, brs), 7.95 (2H, d, J=9 Hz), 7.89 (1H, brt, J=6 Hz), 7.47 (2H,d, J=9 Hz), 7.34-7.28 (4H, m), 7.23-7.20 (1H, m), 7.17 (1H, s), 7.03(2H, d, J=9 Hz), 6.98 (2H, d, J=9 Hz), 4.61 (1H, brt, J=5 Hz), 4.27 (2H,t, J=7 Hz), 3.81 (1H, quint, J=3 Hz), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q,J=6 Hz), 3.06 (2H, t, J=7 Hz), 0.78-0.73 (2H, m), 0.63-0.59 (2H, m).

Example 53N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropylphenyl)vinyl]-4-(2-phenylethoxy)benzamideExemplary Compound No. 1-120

The same reaction as in Example 9 (9c) was conducted usingN-[4-(2-phenylethoxy)benzoyl]glycine (187 mg) prepared in Example 47(47a) and 4-isopropylbenzaldehyde (104 μL) to give the correspondingoxazolone (147 mg). Then, the same reaction as in Example 9 (9d) wasconducted using all this oxazolone to give 114 mg of the title compound(white amorphous solid).

MS (FAB) m/z: 473 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.69 (1H, s), 7.95-7.90 (3H, m), 7.44 (2H, d, J=8 Hz), 7.34-7.28 (4H,m), 7.24-7.22 (1H, m), 7.18 (2H, d, J=9 Hz), 7.16 (1H, s), 7.04 (2H, d,J=9 Hz), 4.61 (1H, t, J=5 Hz), 4.28 (2H, t, J=7 Hz), 3.42 (2H, q, J=6Hz), 3.21 (2H, q, J=6 Hz), 3.06 (2H, t, J=7 Hz), 2.83 (1H, sept, J=7Hz), 1.16 (6H, d, J=7 Hz).

Example 54N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(3,3,3-trifluoropropoxy)benzamideExemplary Compound No. 1-274

(54a) N-[4-(3,3,3-Trifluoropropoxy)benzoyl]glycine

The same reactions as in Example 9 (9a) and (9b) were conducted usingmethyl 4-hydroxybenzoate (1.52 g, 9.99 mmol) and3,3,3-trifluoropropan-1-ol (1.14 g, 9.99 mmol) to give 385 mg of thetitle compound (white powder, yield: 14%).

(54b)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(3,3,3-trifluoropropoxy)benzamide

The same reaction as in Example 9 (9c) was conducted usingN-[4-(3,3,3-trifluoropropoxy)benzoyl]glycine (291 mg) prepared inExample 54 (54a) and 4-isopropoxybenzaldehyde (173 mg) to give thecorresponding oxazolone (240 mg). Then, the same reaction as in Example9 (9d) was conducted using 76 mg of this oxazolone to give 69 mg of thetitle compound (white powder).

mp: 84 to 86° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.76 (1H, brs), 7.79 (2H, d, J=9 Hz), 7.32 (1H, brt, J=6 Hz), 7.20 (2H,d, J=9 Hz), 6.78 (2H, d, J=9 Hz), 6.77 (1H, s), 6.68 (2H, d, J=9 Hz),4.45 (1H, sept, J=6 Hz), 4.15 (2H, t, J=6 Hz), 3.74 (1H, brs), 3.54 (2H,brs), 3.24 (2H, q, J=4 Hz), 2.66-2.55 (2H, m), 1.28 (6H, d, J=6 Hz).

Example 55N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(3,3,3-trifluoropropoxy)benzamideExemplary Compound No. 1-279

The same reaction as in Example 9 (9c) was conducted usingN-[4-(3,3,3-trifluoropropoxy)benzoyl]glycine (1.46 g) prepared inExample 54 (54a) and 4-cyclopropylbenzaldehyde (768 mg) prepared inExample 5 to give the corresponding oxazolone (1.72 g). Then, the samereaction as in Example 9 (9d) was conducted using all this oxazolone1.22 g of the title compound (white powder).

mp: 185 to 187° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm: 9.69(1H, brs), 7.96 (2H, d, J=9 Hz), 7.93 (1H, brt, J=5 Hz), 7.39 (2H, d,J=8 Hz), 7.15 (1H, s), 7.06 (2H, d, J=9 Hz), 7.00 (2H, d, J=8 Hz), 4.61(1H, t, J=5 Hz), 4.29 (2H, t, J=6 Hz), 3.43 (2H, q, J=6 Hz), 3.22 (2H,q, J=6 Hz), 2.88-2.77 (2H, m), 1.90-1.83 (1H, m), 0.95-0.91 (2H, m),0.67-0.64 (2H, m).

Example 56N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenoxyethoxy)benzamideExemplary Compound No. 1-313

(56a) N-[4-(2-Phenoxyethoxy)benzoyl]glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (249 mg, 0.991 mmol)prepared in Example 1 (1a) and 2-phenoxyethanol (163 μL, 1.19 mmol) togive 241 mg of the title compound (white powder, yield: 78%).

(56b)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenoxyethoxy)benzamide

The same reaction as in Example 1 (1c) was conducted usingN-[4-(2-phenoxyethoxy)benzoyl]glycine (241 mg) prepared in Example 56(56a) and 4-isopropoxybenzaldehyde (133 μL) to give the correspondingoxazolone (250 mg). Then, the same reaction as in Example 1 (1d) wasconducted using all this oxazolone to give 129 mg of the title compound(white amorphous solid).

MS (FAB) m/z: 505 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.66 (1H, brs), 7.97 (2H, d, J=9 Hz), 7.88 (1H, brt, J=6 Hz), 7.45 (2H,d, J=9 Hz), 7.29 (2H, dd, J=9 Hz, 7 Hz), 7.16 (1H, s), 7.09 (2H, d, J=9Hz), 6.98 (2H, d, J=9 Hz), 6.94 (1H, t, J=7 Hz), 6.84 (2H, d, J=7 Hz),4.64-4.58 (2H, m), 4.42-4.40 (2H, m), 4.35-4.32 (2H, m), 3.43 (2H, q,J=6 Hz), 3.22 (2H, q, J=6 Hz), 1.23 (6H, d, J=6 Hz).

Example 57N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(2-phenoxyethoxy)benzamideExemplary Compound No. 1-317

The same reaction as in Example 1 (1c) was conducted usingN-[4-(2-phenoxyethoxy)benzoyl]glycine (157 mg) prepared in Example 56(56a) and 4-(trifluoromethoxy)benzaldehyde (69 μL) to give thecorresponding oxazolone (176 mg). The same reaction as in Example 1 (1d)was conducted using 175 mg of this oxazolone to give 58 mg of the titlecompound (white amorphous solid).

MS (ESI) m/z: 531 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.81 (1H, brs), 8.08 (1H, brt, J=6 Hz), 7.97 (2H, d, J=9 Hz), 7.65 (2H,d, J=9 Hz), 7.34 (2H, d, J=9 Hz), 7.31 (2H, d, J=8 Hz), 7.17 (1H, s),7.11 (2H, d, J=8 Hz), 7.00 (2H, d, J=9 Hz), 6.96 (1H, t, J=7 Hz), 4.64(1H, brt, J=5 Hz), 4.43-4.41 (2H, m), 4.35-4.33 (2H, m), 3.45 (2H, q J=6Hz), 3.24 (2H, q, J=6 Hz).

Example 58N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(2-phenoxyethoxy)benzamideExemplary Compound No. 1-316

The same reaction as in Example 1 (I c) was conducted usingN-[4-(2-phenoxyethoxy)benzoyl]glycine (157 mg) prepared in Example 56(56a) and 4-cyclopropylbenzaldehyde (71 mg) prepared in Example 5 togive the corresponding oxazolone (166 mg). The same reaction as inExample 1 (1d) was conducted using 165 mg of this oxazolone to give 62mg of the title compound (light yellow amorphous solid).

MS (ESI) m/z: 487 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.72 (1H, brs), 8.00-7.94 (3H, m), 7.42 (2H, d, J=8 Hz), 7.32 (2H, t,J=8 Hz), 7.18 (1H, s), 7.11 (2H, d, J=8 Hz), 7.05-6.95 (5H, m), 4.63(1H, brt, J=5 Hz), 4.43-4.40 (2H, m), 4.36-4.33 (2H, m), 3.44 (2H, q,J=6 Hz), 3.23 (2H, q, J=6 Hz), 1.91-1.84 (1H, m), 0.96-0.91 (2H, m),0.68-0.64 (2H, m).

Example 594-(3-Cyclopropylpropoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamideExemplary Compound No. 1-323

(59a) N-[4-(3-Cyclopropylpropoxy)benzoyl]glycine

The same reactions as in Example 9 (9a) and (9b) were conducted usingmethyl 4-hydroxybenzoate (6.09 g, 40.0 mmol) and3-cyclopropylpropan-1-ol (which is the compound disclosed in Helv. Chim.Acta, (2003), 86, 865-893, 4.41 g, 44.0 mmol) to give 5.74 g of thetitle compound (white powder, yield: 51%).

(59b)4-(3-Cyclopropylpropoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

The same reaction as in Example 9 (9c) was conducted usingN-[4-(3-cyclopropylpropoxy)benzoyl]glycine (139 mg) prepared in Example59 (59a) and 4-isopropoxybenzaldehyde (86 mg) to give the correspondingoxazolone (124 mg). Then, the same reaction as in Example 9 (9d) wasconducted using 91 mg of this oxazolone to give 63 mg of the titlecompound (white powder).

mp: 64 to 66° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.29 (1H, brs), 7.81 (2H, d, J=9 Hz), 7.28 (2H, d, J=9 Hz), 7.07 (1H,brt, J=6 Hz), 6.95 (1H, s), 6.86 (2H, d, J=9 Hz), 6.75 (2H, d, J=9 Hz),4.50 (1H, sept, J=6 Hz), 4.01 (2H, t, J=6 Hz), 3.64 (2H, t, J=5 Hz),3.36 (2H, q, J=5 Hz), 1.90 (2H, quint, J=7 Hz), 1.38 (2H, q, J=7 Hz),1.31 (6H, d, J=6 Hz), 0.75-0.67 (1H, m), 0.47-0.43 (2H, m), 0.07-0.04(2H, m).

Example 604-(3-Cyclopropylpropoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamideExemplary Compound No. 1-327

The same reaction as in Example 9 (9c) was conducted usingN-[4-(3-cyclopropylpropoxy)benzoyl]glycine (277 mg) prepared in Example59 (59a) and 4-(trifluoromethoxy)benzaldehyde (150 μL) to give thecorresponding oxazolone (224 mg). Then, the same reaction as in Example9 (9d) was conducted using 151 mg of this oxazolone to give 123 mg ofthe title compound (colorless amorphous solid).

MS (FAB) m/z: 493 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (500 MHz, CDCl₃) δ ppm:

7.91 (1H, brs), 7.78 (2H, d, J=9 Hz), 7.40 (2H, d, J=9 Hz), 7.16 (2H, d,J=8 Hz), 7.01 (1H, s), 6.92 (2H, d, J=9 Hz), 6.78 (1H, t, J=5 Hz), 4.05(2H, t, J=6 Hz), 3.78 (2H, brq, J=4 Hz), 3.49 (2H, q, J=4 Hz), 3.05 (1H,brt, J=6 Hz), 1.92 (2H, quint, J=7 Hz), 1.39 (2H, q, J=7 Hz), 0.74-0.67(1H, m), 0.47-0.43 (2H, m), 0.07-0.04 (2H, m).

Example 614-(3-Cyclopropylpropoxy)-N-((Z)-2-[4-(2,2-difluoroethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-330

The same reaction as in Example 9 (9c) was conducted usingN-[4-(3-cyclopropylpropoxy)benzoyl]glycine (277 mg) prepared in Example59 (59a) and 4-(2,2-difluoroethoxy)benzaldehyde (196 mg) prepared inExample 4 (4a) to give the corresponding oxazolone (244 mg). Then, thesame reaction as in Example 9 (9d) was conducted using 150 mg of thisoxazolone to give 84 mg of the title compound (white powder).

mp: 149 to 151° C.;

¹H-nuclear magnetic resonance spectrum (500 MHz, CDCl₃) δ ppm:

7.81-7.79 (3H, m), 7.36 (2H, d, J=9 Hz), 7.06 (1H, s), 6.93 (2H, d, J=9Hz), 6.86 (2H, d, J=8 Hz), 6.74 (1H, t, J=6 Hz), 6.07 (1H, tt, J=55 Hz,4 Hz), 4.16 (2H, td, J=13 Hz, 4 Hz), 4.05 (2H, t, J=7 Hz), 3.77 (2H, t,J=5 Hz), 3.50 (2H, q, J=5 Hz), 1.92 (2H, quint, J=7 Hz), 1.39 (2H, q,J=7 Hz), 0.76-0.68 (1H, m), 0.47-0.44 (2H, m), 0.07-0.04 (2H, m).

Example 62N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(3-cyclopropylpropoxy)benzamideExemplary Compound No. 1-326

The same reaction as in Example 9 (9c) was conducted usingN-[4-(3-cyclopropylpropoxy)benzoyl]glycine (277 mg) prepared in Example59 (59a) and 4-cyclopropylbenzaldehyde (154 mg) prepared in Example 5 togive the corresponding oxazolone (260 mg). Then, the same reaction as inExample 9 (9d) was conducted using 151 mg of this oxazolone to give 148mg of the title compound (white powder).

mp: 170 to 171° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.80 (2H, d, J=9 Hz), 7.67 (1H, brs), 7.29 (2H, d, J=8 Hz), 7.06 (1H,s), 7.03 (2H, d, J=9 Hz), 6.94 (2H, d, J=8 Hz), 6.61 (1H, brt, J=5 Hz),4.06 (2H, t, J=7 Hz), 3.79 (2H, brs), 3.51 (2H, q, J=5 Hz), 3.09 (1H,brs), 1.96-1.84 (3H, m), 1.39 (2H, q, J=7 Hz), 1.02-0.97 (2H, m),0.73-0.68 (3H, m), 0.47-0.43 (2H, m), 0.07-0.04 (2H, m).

Example 63N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(2-thienylethoxy)]benzamideExemplary Compound No. 1-283

(63a) N-{4-[2-(2-Thienyl)ethoxy]benzoyl}glycine

The same reactions as in Example 9 (9a) and (9b) were conducted usingmethyl 4-hydroxybenzoate (1.55 g, 10.2 mmol) and 2-(2-thienyl)ethanol(1.20 mL, 10.8 mmol) to give 2.02 g of the title compound (white powder,yield: 65%).

[In this case, a 2 N sodium hydroxide aqueous solution was used insteadof a 2 M lithium hydroxide aqueous solution.]

(63b)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(2-thienylethoxy)]benzamide

The same reaction as in Example 9 (9c) was conducted usingN-{4-[2-(2-thienyl)ethoxy]benzoyl}glycine (251 mg) prepared in Example63 (63a) and 4-isopropoxybenzaldehyde (139 μL) to give the correspondingoxazolone (191 mg). Then, the same reaction as in Example 9 (9d) wasconducted using all this oxazolone to give 134 mg of the title compound(white amorphous solid).

MS (FAB) m/z: 495 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.65 (1H, brs), 7.96 (2H, d, J=9 Hz), 7.87 (1H, brt, J=6 Hz), 7.45 (2H,d, J=9 Hz), 7.35 (1H, dd, J=5 Hz, 2 Hz), 7.16 (1H, s), 7.05 (2H, d, J=9Hz), 6.99-6.95 (2H, m), 6.84 (2H, d, J=9 Hz), 4.63-4.57 (2H, m), 4.27(2H, t, J=6H), 3.42 (2H, q, J=6 Hz), 3.28 (2H, t, J=6 Hz), 3.21 (2H, q,J=6 Hz), 1.22 (6H, d, J=6 Hz).

Example 64N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(2-thienyl)ethoxy]benzamideExemplary Compound No. 1-288

The same reaction as in Example 9 (9c) was conducted usingN-{4-[2-(2-thienyl)ethoxy]benzoyl}glycine (279 mg) prepared in Example63 (63a) and 4-cyclopropylbenzaldehyde (171 mg) prepared in Example 5 togive the corresponding oxazolone (268 mg). Then, the same reaction as inExample 9 (9d) was conducted using all this oxazolone to give 124 mg ofthe title compound (white amorphous solid).

MS (FAB) m/z: 477 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.71 (1H, s), 7.98-7.94 (3H, m), 7.41 (2H, d, J=8 Hz), 7.37 (1H, dd, J=5Hz, 1 Hz), 7.17 (1H, s), 7.07 (2H, d, J=9 Hz), 7.02 (2H, d, J=8 Hz),7.00-6.97 (2H, m), 4.63 (1H, t, J=5 Hz), 4.29 (2H, t, J=6 Hz), 3.43 (2H,q, J=6 Hz), 3.29 (2H, t, J=6 Hz), 3.22 (2H, q, J=6 Hz), 1.90-1.84 (1H,m), 0.95-0.91 (2H, m), 0.67-0.64 (2H, m).

Example 65N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[2-(1H-pyrrol-1-yl)ethoxy]benzamideExemplary Compound No. 1-295

(65a) N-{4-[2-(1H-Pyrrol-1-yl)ethoxy]benzoyl}glycine

The same reaction as in Example 23 (23a) was conducted using methyl4-hydroxybenzoate (913 mg, 6.00 mmol) and 2-(1H-pyrrol-1-yl)ethanol (692μL, 6.60 mmol) to give the corresponding benzoic acid derivative (1.23g, yield: 89%). Then, the same reaction as in Example 23 (23b) wasconducted using 578 mg (2.50 mmol) of this derivative to give 568 mg ofthe title compound (colorless crystalline solid, yield: 79%).

(65b)N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[2-(1H-pyrrol-1-yl)ethoxy]benzamide

The same reaction as in Example 23 (23c) was conducted usingN-{4-[2-(1H-pyrrol-1-yl)ethoxy]benzoyl}glycine (120 mg) prepared inExample 65 (65a) and 4-(trifluoromethoxy)benzaldehyde (63 μL) to givethe corresponding oxazolone (128 mg). Then, the same reaction as inExample 23 (23d) was conducted using all this oxazolone to give 91 mg ofthe title compound (white amorphous solid).

MS (FAB) m/z: 504 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.36 (1H, brs), 7.75 (2H, d, J=8 Hz), 7.35 (2H, d, J=9 Hz), 7.10 (2H, d,J=8 Hz), 7.01 (1H, t, J=6 Hz), 6.87 (1H, s), 6.82 (2H, d, J=9 Hz), 6.75(2H, t, J=2 Hz), 6.18 (2H, t, J=2 Hz), 4.28 (2H, t, J=5 Hz), 4.20 (2H,t, J=5 Hz), 3.70 (2H, t, J=5 Hz), 3.39 (2H, q, J=5 Hz), 3.26 (1H, brs).

Example 66N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(1H-pyrrol-1-yl)ethoxy]benzamideExemplary Compound No. 1-297

The same reaction as in Example 23 (23c) was conducted usingN-{4-[2-(1H-pyrrol-1-yl)ethoxy]benzoyl}glycine (173 mg) prepared inExample 65 (65a) and 4-cyclopropylbenzaldehyde (92 mg) prepared inExample 5 to give the corresponding oxazolone (178 mg). Then, the samereaction as in Example 23 (23d) was conducted using all this oxazoloneto give 118 mg of the title compound (light yellow amorphous solid).

MS (FAB) m/z: 460 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.67 (1H, brs), 7.93 (2H, d, J=9 Hz), 7.92 (1H, t, J=6 Hz), 7.38 (2H, d,J=9 Hz), 7.14 (1H, s), 7.01 (2H, d, J=9 Hz), 6.99 (2H, d, J=9 Hz), 6.82(2H, t, J=2 Hz), 5.98 (2H, t, J=2 Hz), 4.61 (1H, t, J=5 Hz), 4.32-4.26(4H, m), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 1.89-1.83 (1H, m),0.95-0.90 (2H, m), 0.67-0.63 (2H, m).

Example 67N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(3-methoxyphenyl)ethoxy]benzamideExemplary Compound No. 1-146

(67a) N-{4-[2-(3-Methoxyphenyl)ethoxy]benzoyl}glycine

The same reactions as in Example 9 (9a) and (9b) were conducted usingmethyl 4-hydroxybenzoate (4.26 g, 28.0 mmol) and2-(3-methoxyphenyl)ethanol (4.32 mL, 31.0 mmol) to give 8.54 g of thetitle compound (colorless crystal, yield: 92%).

(67b)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(3-methoxyphenyl)ethoxy]benzamide

The same reaction as in Example 9 (9c) was conducted usingN-{4-[2-(3-methoxyphenyl)ethoxy]benzoyl}glycine (264 mg) prepared inExample 67 (67a) and 4-isopropoxybenzaldehyde (138 mg) to give thecorresponding oxazolone (236 mg). Then, the same reaction as in Example9 (9d) was conducted using 151 mg of this oxazolone to give 138 mg ofthe title compound (white amorphous solid).

MS (FAB) m/z: 519 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.31 (1H, brs), 7.70 (2H, d, J=9 Hz), 7.17-7.12 (3H, m), 7.05 (1H, brt,J=6 Hz), 6.81 (1H, s), 6.78-6.69 (5H, m), 6.63 (2H, d, J=9 Hz), 4.39(1H, sept, J=6 Hz), 4.08 (2H, t, J=7 Hz), 3.72 (3H, s), 3.57 (1H, brd,J=5 Hz), 3.53 (2H, brd, J=4 Hz), 3.24 (2H, q, J=4 Hz), 2.98 (2H, t, J=7Hz), 1.21 (6H, d, J=6 Hz).

Example 68N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[2-(3-methoxyphenyl)ethoxy]benzamideExemplary Compound No. 1-149

The same reaction as in Example 9 (9c) was conducted usingN-{4-[2-(3-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg) prepared inExample 67 (67a) and 4-(trifluoromethoxy)benzaldehyde (200 mg) to givethe corresponding oxazolone (416 mg). Then, the same reaction as inExample 9 (9d) was conducted using 121 mg of this oxazolone to give 96mg of the title compound (colorless amorphous solid).

MS (FAB) m/z: 545 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.80 (1H, brs), 8.08 (1H, t, J=6 Hz), 7.97 (2H, d, J=9 Hz), 7.65 (2H, d,J=9 Hz), 7.34 (2H, d, J=8 Hz), 7.23 (1H, t, J=8 Hz), 7.18 (1H, s), 7.06(2H, d, J=9 Hz), 6.93 (1H, s), 6.91 (1H, d, J=9 Hz), 6.81 (1H, dd, J=8Hz, 2 Hz), 4.65 (1H, t, J=6 Hz), 4.29 (2H, t, J=7 Hz), 3.75 (3H, s),3.47 (2H, q, J=6 Hz), 3.25 (2H, q, J=6 Hz), 3.04 (2H, t, J=7 Hz).

Example 69N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(3-methoxyphenyl)ethoxy]benzamideExemplary Compound No. 1-155

The same reaction as in Example 9 (9c) was conducted usingN-{4-[2-(3-methoxyphenyl)ethoxy]benzoyl}glycine (231 mg) prepared inExample 67 (67a) and 4-cyclopropylbenzaldehyde (108 mg) prepared inExample 5 to give the corresponding oxazolone (249 mg). Then, the samereaction as in Example 9 (9d) was conducted using 101 mg of thisoxazolone to give 97 mg of the title compound (white amorphous solid).

MS (FAB) m/z: 501 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.69 (1H, brs), 7.96 (2H, d, J=9 Hz), 7.94 (1H, t, J=5 Hz), 7.41 (2H, d,J=8 Hz), 7.23 (1H, t, J=8 Hz), 7.17 (1H, s), 7.05 (2H, d, J=8 Hz), 7.02(2H, d, J=8 Hz), 6.92-6.90 (2H, m), 6.81 (1H, dd, J=8 Hz, 2 Hz), 4.62(1H, t, J=6 Hz), 4.28 (2H, t, J=7 Hz), 3.75 (3H, s), 3.44 (2H, q, J=6Hz), 3.23 (2H, q, J=6 Hz), 3.04 (2H, t, J=7 Hz), 1.87 (1H, sept, J=5Hz), 0.95-0.91 (2H, m), 0.67-0.64 (2H, m).

Example 70N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(3-methoxyphenyl)ethoxy]benzamideExemplary Compound No. 1-161

The same reaction as in Example 9 (9c) was conducted usingN-{4-[2-(3-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg) prepared inExample 67 (67a) and 4-chlorobenzaldehyde (148 mg) to give thecorresponding oxazolone (396 mg). Then, the same reaction as in Example9 (9d) was conducted using 108 mg of this oxazolone to give 90 mg of thetitle compound (white powder).

mp: 54 to 56° C.;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.76 (1H, brs), 8.06 (1H, t, J=6 Hz), 7.95 (2H, d, J=9 Hz), 7.53 (2H, d,J=9 Hz), 7.39 (2H, d, J=8 Hz), 7.23 (1H, t, J=8 Hz), 7.15 (1H, s), 7.05(2H, d, J=9 Hz), 6.92 (1H, s), 6.91 (1H, d, J=9 Hz), 6.81 (1H, dd, J=8Hz, 2 Hz), 4.64 (1H, t, J=6 Hz), 4.28 (2H, t, J=7 Hz), 3.75 (3H, s),3.45 (2H, q, J=6 Hz), 3.24 (2H, q, J=6 Hz), 3.04 (2H, t, J=7 Hz).

Example 714-[2-(1,3-Benzodioxol-5-yl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamideExemplary Compound No. 1-331

(71a) N-{4-[2-(1,3-Benzodioxol-5-yl)ethoxy]benzoyl}glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (300 mg, 1.19 mmol)prepared in Example 1 (1a) and 2-(1,3-benzodioxol-5-yl)ethanol (which isthe compound disclosed in Tetrahedron, (2003), 59, 3369-3378, 239 mg,1.44 mmol) to give 356 mg of the title compound (pale red powder, yield:87%).

(71b)4-[2-(1,3-Benzodioxol-5-yl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(1,3-benzodioxol-5-yl)ethoxy]benzoyl}glycine (179 mg) preparedin Example 71 (71a) and 4-isopropoxybenzaldehyde (95 μL) to give thecorresponding oxazolone (212 mg). Then, the same reaction as in Example1 (1d) was conducted using all this oxazolone to give 94 mg of the titlecompound (light yellow amorphous solid).

MS (FAB) m/z: 533 [M+H]+

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.64 (1H, brs), 7.95 (2H, d, J=9 Hz), 7.86 (1H, t, J=6 Hz), 7.45 (2H, d,J=9 Hz), 7.16 (1H, s), 7.03 (2H, d, J=9 Hz), 6.93 (1H, d, J=2 Hz), 6.85(1H, d, J=2 Hz), 6.83 (2H, s), 6.77 (1H, dd, J=8 Hz, 2 Hz), 5.96 (2H,s), 4.63-4.57 (2H, m), 4.22 (2H, t, J=7 Hz), 3.42 (2H, t, J=6 Hz), 3.21(2H, q, J=6 Hz), 2.98 (2H, t, J=7 Hz), 1.23 (6H, d, J=6 Hz).

Example 724-[2-(1,3-Benzodioxol-5-yl)ethoxy]-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-334

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(1,3-benzodioxol-5-yl)ethoxy]benzoyl}glycine (180 mg) preparedin Example 71 (71a) and 4-cyclopropylbenzaldehyde (95 mg) prepared inExample 5 to give the corresponding oxazolone (192 mg). Then, the samereaction as in Example 1 (1d) was conducted using all this oxazolone togive 123 mg of the title compound (white powder).

mp: 113 to 115° C.;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.69 (1H, brs), 7.95 (2H, d, J=8 Hz), 7.94 (1H, t, J=6 Hz), 7.41 (2H, d,J=8 Hz), 7.17 (1H, s), 7.04 (2H, d, J=9 Hz), 7.02 (2H, d, J=8 Hz), 6.95(1H, d, J=1 Hz), 6.85 (1H, d, J=8 Hz), 6.79 (1H, dd, J=8 Hz, 1 Hz), 5.98(2H, s), 4.62 (1H, brt, J=5 Hz), 4.23 (2H, t, J=7 Hz), 3.43 (2H, q, J=6Hz), 3.22 (2H, q, J=6 Hz), 2.98 (2H, t, J=7 Hz), 1.87 (1H, quint, J=3Hz), 095-0.91 (2H, m), 0.67-0.64 (2H, m).

Example 734-[2-(4-Fluorophenyl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamideExemplary Compound No. 1-214

(73a) N-{4-[2-(4-Fluorophenyl)ethoxy]benzoyl}glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (249 mg, 0.991 mmol)prepared in Example 1 (1a) and 2-(4-fluorophenyl)ethanol (150 μL, 1.20mmol) to give 241 mg of the title compound (yield: 91%).

(73b)₄-[2-(4-Fluorophenyl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-fluorophenyl)ethoxy]benzoyl}glycine (250 mg) prepared inExample 73 (73a) and 4-isopropoxybenzaldehyde (137 μL) to give thecorresponding oxazolone (215 mg). Then, the same reaction as in Example1 (1d) was conducted using all this oxazolone to give 122 mg of thetitle compound (white amorphous solid).

MS (FAB) m/z: 507 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.64 (1H, brs), 7.95 (2H, d, J=9 Hz), 7.86 (1H, brt, J=6 Hz), 7.45 (2H,d, J=9 Hz), 7.36 (2H, dd, J=9 Hz, 6 Hz), 7.16 (1H, s), 7.12 (2H, t, J=9Hz), 7.03 (2H, d, J=9 Hz), 6.84 (2H, d, J=9 Hz), 4.63-4.57 (2H, m), 4.26(2H, t, J=7 Hz), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 3.05 (2H,t, J=7 Hz), 1.22 (6H, d, J=6 Hz).

Example 744-[2-(4-Fluorophenyl)ethoxy]-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamideExemplary Compound No. 1-217

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-fluorophenyl)ethoxy]benzoyl}glycine (317 mg) prepared inExample 73 (73a) and 4-(trifluoromethoxy)benzaldehyde (200 mg) to givethe corresponding oxazolone (360 mg). Then, the same reaction as inExample 1 (1d) was conducted using 109 mg of this oxazolone to give 92mg of the title compound (colorless amorphous solid).

MS (FAB) m/z: 533 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.79 (1H, brs), 8.07 (1H, t, J=5 Hz), 7.95 (2H, d, J=8 Hz), 7.64 (2H, d,J=9 Hz), 7.38 (2H, dd, J=8 Hz, 6 Hz), 7.34 (2H, d, J=8 Hz), 7.16 (1H,s), 7.14 (2H, t, J=9 Hz), 7.05 (2H, d, J=9 Hz), 4.64 (1H, t, J=5 Hz),4.27 (2H, t, J=7 Hz), 3.45 (2H, q, J=6 Hz), 3.24 (2H, q, J=6 Hz), 3.06(2H, t, J=7 Hz).

Example 75N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-fluorophenyl)ethoxy]benzamideExemplary Compound No. 1-223

The same reaction as in Example 1 (I c) was conducted usingN-{4-[2-(4-fluorophenyl)ethoxy]benzoyl}glycine (254 mg) prepared inExample 73 (73a) and 4-cyclopropylbenzaldehyde (130 mg) prepared inExample 5 to give the corresponding oxazolone (226 mg). Then, the samereaction as in Example 1 (1d) was conducted using all this oxazolone togive 166 mg of the title compound (white amorphous solid).

MS (FAB) m/z: 489 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.67 (1H, s), 7.95-7.91 (3H, m), 7.40-7.34 (4H, m), 7.15 (1H, s), 7.13(2H, t, J=9 Hz), 7.03 (2H, d, J=9 Hz), 6.99 (2H, d, J=9 Hz), 4.61 (1H,t, J=5 Hz), 4.26 (2H, t, J=7 Hz), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q, J=6Hz), 3.05 (2H, t, J=7 Hz), 1.90-1.83 (1H, m), 0.95-0.90 (2H, m),0.67-0.63 (2H, m).

Example 76N-((Z)-2-[4-(Cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-fluorophenyl)ethoxy]benzamideExemplary Compound No. 1-215

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-fluorophenyl)ethoxy]benzoyl}glycine (203 mg) prepared inExample 73 (73a) and 4-(cyclopropyloxy)benzaldehyde (116 mg) prepared inExample 6 (6c) to give the corresponding oxazolone (179 mg). Then, thesame reaction as in Example 1 (1d) was conducted using all thisoxazolone to give 132 mg of the title compound (white amorphous solid).

MS (FAB) m/z: 505 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.65 (1H, s), 7.95 (2H, d, J=9 Hz), 7.89 (1H, brt, J=6 Hz), 7.47 (2H, d,J=9 Hz), 7.36 (2H, dd, J=9 Hz, 6 Hz), 7.17 (1H, s), 7.12 (2H, t, J=9Hz), 7.03 (2H, d, J=9 Hz), 6.98 (2H, d, J=9 Hz), 4.62 (1H, t, J=5 Hz),4.26 (2H, t, J=7 Hz), 3.81 (1H, sept, J=3 Hz), 3.42 (2H, q, J=6 Hz),3.21 (2H, q, J=6 Hz), 3.05 (2H, t, J=7 Hz), 0.78-0.73 (2H, m), 0.63-0.59(2H, m).

Example 77N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-fluorophenyl)ethoxy]benzamideExemplary Compound No. 1-229

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-fluorophenyl)ethoxy]benzoyl}glycine (317 mg) prepared inExample 73 (73a) and 4-chlorobenzaldehyde (148 mg) to give thecorresponding oxazolone (342 mg). Then, the same reaction as in Example1 (1d) was conducted using 110 mg of this oxazolone to give 98 mg of thetitle compound (white powder).

mp: 60 to 63° C.;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.76 (1H, brs), 8.06 (1H, t, J=5 Hz), 7.95 (2H, d, J=9 Hz), 7.54 (2H, d,J=8 Hz), 7.40-7.37 (4H, m), 7.15 (1H, s), 7.15 (2H, t, J=9 Hz), 7.05(2H, d, J=9 Hz), 4.64 (1H, t, J=5 Hz), 4.27 (2H, t, J=7 Hz), 3.45 (2H,q, J=6 Hz), 3.24 (2H, q, J=6 Hz), 3.06 (2H, t, J=7 Hz).

Example 784-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-199

(78a) N-{4-[2-(4-Chlorophenyl)ethoxy]benzoyl}glycine

(Tributylphosphoranylidene)acetonitrile (1.31 g, 4.89 mmol) was added toa solution of toluene (12 mL) containing N-(4-hydroxybenzoyl)glycineethyl ester (which is the compound disclosed in J. Med. Chem., (1999),42, 1041-1052, 663 mg, 2.97 mmol) and 2-(4-chlorophenyl)ethanol (447 μL,3.30 mmol). The mixture was stirred at 100° C. for 4 hours, and thenethyl acetate was added thereto. The resulting mixture was washed withwater and saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the resulting residue was purified bysilica gel column chromatography (hexane to hexane:ethyl acetate, 4:1 to3:1, and then ethyl acetate, v/v) to give a powder (1.23 g). All thispowder was dissolved in ethanol (12 mL), and then a 2 M lithiumhydroxide aqueous solution (3.00 mL, 6.00 mmol) was added thereto. Theresulting mixture was stirred at 60° C. for 30 minutes, and then 10%hydrochloric acid (2.1 mL) was added thereto under ice-cooling. Theproduced precipitate was collected by filtration, washed sequentiallywith water and diisopropyl ether, and then dried under reduced pressureto give 861 mg of the title compound (powder, yield: 87%).

(78b)4-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (267 mg) prepared inExample 78 (78a) and 4-(difluoromethoxy)benzaldehyde (111 μL) to givethe corresponding oxazolone (333 mg). Then, the same reaction as inExample 1 (1d) was conducted using 118 mg of this oxazolone to give 91mg of the title compound (white powder).

mp: 160 to 162° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.71 (1H, brs), 8.00 (1H, brt, J=6 Hz), 7.92 (2H, d, J=9 Hz), 7.56 (2H,d, J=9 Hz), 7.35 (4H, s), 7.23 (1H, t, J=74 Hz), 7.16 (1H, s), 7.11 (2H,d, J=9 Hz), 7.02 (2H, d, J=9 Hz), 4.62 (1H, t, J=5 Hz), 4.26 (2H, t, J=7Hz), 3.43 (2H, q, J=6 Hz), 3.22 (2H, q, J=6 Hz), 3.05 (2H, t, J=7 Hz).

Example 794-[2-(4-Chlorophenyl)ethoxy]-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamideExemplary Compound No. 1-200

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (234 mg) prepared inExample 78 (78a) and 4-(trifluoromethoxy)benzaldehyde (110 μL) to givethe corresponding oxazolone (208 mg). Then, the same reaction as inExample 1 (1d) was conducted using all this oxazolone to give 160 mg ofthe title compound (white amorphous solid).

MS (FAB) m/z: 549 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.76 (1H, s), 8.04 (1H, brt, J=5 Hz), 7.92 (2H, d, J=9 Hz), 7.61 (2H, d,J=9 Hz), 7.35 (4H, s), 7.31 (2H, d, J=9 Hz), 7.14 (1H, s), 7.02 (2H, d,J=9 Hz), 4.62 (1H, t, J=5 Hz), 4.26 (2H, t, J=7 Hz), 3.43 (2H, q, J=6Hz), 3.22 (2H, q, J=6 Hz), 3.06 (2H, t, J=7 Hz).

Example 804-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-206

The same reaction as in Example 1 (I c) was conducted usingN-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (238 mg) prepared inExample 78 (78a) and 4-cyclopropylbenzaldehyde (124 mg) prepared inExample 5 to give the corresponding oxazolone (215 mg). Then, the samereaction as in Example 1 (1d) was conducted using all this oxazolone togive 173 mg of the title compound (white amorphous solid).

MS (FAB) m/z: 505 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.69 (1H, s), 7.97-7.93 (3H, m), 7.41 (2H, d, J=8 Hz), 7.38 (4H, s),7.17 (1H, s), 7.05 (2H, d, J=9 Hz), 7.01 (2H, d, J=8 Hz), 4.63 (1H, t,J=5 Hz), 4.28 (2H, t, J=6 Hz), 3.44 (2H, q, J=6 Hz), 3.23 (2H, q, J=6Hz), 3.07 (2H, t, J=6 Hz), 1.89-1.84 (1H, m), 0.95-0.91 (2H, m),0.67-0.64 (2H, m).

Example 814-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-198

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (267 mg) prepared inExample 78 (78a) and 4-(cyclopropyloxy)benzaldehyde (136 mg) prepared inExample 6 (6c) to give the corresponding oxazolone (341 mg). Then, thesame reaction as in Example 1 (1d) was conducted using 115 mg of thisoxazolone to give 79 mg of the title compound (light yellow powder).

mp: 66 to 69° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.65 (1H, brs), 7.95 (2H, d, J=9 Hz), 7.89 (1H, brt, J=6 Hz), 7.47 (2H,d, J=9 Hz), 7.36 (4H, s), 7.17 (1H, s), 7.03 (2H, d, J=9 Hz), 6.97 (2H,d, J=9 Hz), 4.62 (1H, t, J=6 Hz), 4.26 (2H, t, J=7 Hz), 3.81 (1H, sept,J=3 Hz), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 3.06 (2H, t, J=7Hz), 0.78-0.73 (2H, m), 0.63-0.59 (2H, m).

Example 824-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-(4-chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-212

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (267 mg) prepared inExample 78 (78a) and 4-chlorobenzaldehyde (118 mg) to give thecorresponding oxazolone (301 mg). Then, the same reaction as in Example1 (1d) was conducted using 110 mg of this oxazolone to give 50 mg of thetitle compound (colorless crystalline solid).

mp: 137 to 139° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.72 (1H, brs), 8.04 (1H, brt, J=6 Hz), 7.91 (2H, d, J=9 Hz), 7.50 (2H,d, J=9 Hz), 7.37 (2H, d, J=9 Hz), 7.35 (4H, s), 7.11 (1H, s), 7.02 (2H,d, J=9 Hz), 4.63 (1H, t, J=5 Hz), 4.26 (2H, t, J=7 Hz), 3.43 (2H, q, J=6Hz), 3.21 (2H, q, J=6 Hz), 3.06 (2H, t, J=7 Hz).

Example 834-[2-(4-Chlorophenyl)ethoxy]-N-((Z)-2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-96

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-chlorophenyl)ethoxy]benzoyl}glycine (236 mg) prepared inExample 78 (78a) and 4-ethoxybenzaldehyde (107 μL) to give thecorresponding oxazolone (183 mg). Then, the same reaction as in Example1 (1d) was conducted using all this oxazolone to give 124 mg of thetitle compound (white amorphous solid).

MS (FAB) m/z: 509 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.64 (1H, s), 7.94 (2H, d, J=9 Hz), 7.87 (1H, brt, J=6 Hz), 7.45 (2H, d,J=9 Hz), 7.36 (4H, s), 7.16 (1H, s), 7.02 (2H, d, J=9 Hz), 6.85 (2H, d,J=9 Hz), 4.61 (1H, t, J=6 Hz), 4.27 (2H, t, J=7 Hz), 3.99 (2H, q, J=7Hz), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 3.06 (2H, t, J=7 Hz),1.28 (3H, t, J=7 Hz).

Example 844-[2-(4-Cyclopropylphenyl)ethoxy]-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamideExemplary Compound No. 1-240

(84a) Methyl 4-[2-(4-bromophenyl)ethoxy]benzoate

Methyl 4-hydroxybenzoate (1.09 g, 7.14 mmol), 2-(4-bromophenyl)ethanol(1.44 g, 7.14 mmol), and triphenylphosphine (2.06 g, 7.86 mmol) weredissolved in THF (44 mL), and then diethyl azodicarboxylate (3.57 mL,40% toluene solution, 7.86 mmol) was added thereto while stirring underice-cooling. The mixture was further stirred at room temperature for 2days, and then the reaction solution was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate, 19:1 to 9:1, v/v) to give 1.75 g of the titlecompound (white powder, yield: 73%).

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.95 (2H, d, J=9 Hz), 7.42 (2H, d, J=8 Hz), 7.14 (2H, d, J=9 Hz), 6.87(2H, d, J=9 Hz), 4.19 (2H, t, J=7 Hz), 3.87 (3H, s), 3.06 (2H, t, J=7Hz).

(84b) 4-[2-(4-Cyclopropylphenyl)ethoxy]benzoic acid

Cyclopropylization was conducted according to the method disclosed inTetrahedron Lett., (2002), 43, 6987-6990. Cyclopropyl borate (298 mg,3.46 mmol) was dissolved in a mixture solution of toluene (10 mL) andwater (0.54 mL), and methyl 4-[2-(4-bromophenyl)ethoxy]benzoate (893 mg,2.66 mmol) prepared in Example 84 (84a), tricyclohexylphosphine (15%toluene solution, 0.58 mL, 0.266 mmol), potassium phosphate (2.16 g,9.86 mmol), and palladium acetate (45 mg, 0.200 mmol) were addedthereto. The mixture was stirred at 100° C. for 2 hours and then cooledto room temperature. After the addition of ethyl acetate, the mixturewas washed sequentially with water (twice) and saturated brine and driedover anhydrous sodium sulfate. Then, the solvent was evaporated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate, 9:1, v/v) to give the corresponding cyclopropyl derivative (544mg, 1.84 mmol).

All the cyclopropyl derivative was dissolved in ethanol (4.59 mL), and a2 M lithium hydroxide aqueous solution (1.84 mL, 3.67 mmol) was addedthereto. The mixture was stirred at 60° C. for 1 hour and then cooled toroom temperature, and water and 1 N hydrochloric acid (3.67 mL, 3.67mmol) were added thereto. The produced precipitate was collected byfiltration and dried by heating under reduced pressure to give 448 mg ofthe title compound (yield: 60%).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

12.68 (1H, brs), 7.86 (2H, d, J=9 Hz), 7.19 (2H, d, J=8 Hz), 7.01 (2H,d, J=7 Hz), 6.99 (2H, d, J=8 Hz), 4.22 (2H, t, J=7 Hz), 2.99 (2H, t, J=7Hz), 1.88 (1H, quint, J=4 Hz), 0.93-0.89 (2H, m), 0.64-0.60 (2H, m).

(84c) N-{4-[2-(4-Cyclopropylphenyl)ethoxy]benzoyl}glycine

The same reaction as in Example 9 (9b) was conducted using4-[2-(4-cyclopropylphenyl)ethoxy]benzoic acid (444 mg, 1.57 mmol)prepared in Example 84 (84b) to give 492 mg of the title compound (whitepowder, yield: 92%).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

12.56 (1H, brs), 8.67 (1H, brt, J=6 Hz), 7.82 (2H, d, J=9 Hz), 7.20 (2H,d, J=8 Hz), 7.01 (2H, d, J=8 Hz), 7.00 (2H, d, J=8 Hz), 4.21 (2H, t, J=7Hz), 3.88 (2H, d, J=5 Hz), 2.99 (2H, t, J=7 Hz), 1.88 (1H, quint, J=5Hz), 0.93-0.89 (2H, m), 0.65-0.61 (2H, m).

(84d)4-[2-(4-Cyclopropylphenyl)ethoxy]-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide

The same reaction as in Example 9 (9c) was conducted usingN-{4-[2-(4-cyclopropylphenyl)ethoxy]benzoyl}glycine (150 mg) prepared inExample 84 (84c) and 4-cyclopropylbenzaldehyde (68 mg) prepared inExample 5 to give the corresponding oxazolone (100 mg). Then, the samereaction as in Example 9 (9d) was conducted using 97 mg of thisoxazolone to give 77 mg of the title compound (white amorphous solid).

MS (FAB) m/z: 511 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.66 (1H, brs), 7.94-7.90 (3H, m), 7.39 (2H, d, J=8 Hz), 7.19 (2H, d,J=8 Hz), 7.14 (1H, s), 7.03-6.98 (6H, m), 4.61 (1H, t, J=5 Hz), 4.23(2H, t, J=7 Hz), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 3.00 (2H,t, J=7 Hz), 1.91-1.83 (2H, m), 0.95-0.89 (4H, m), 0.67-0.61 (4H, m).

Example 85N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-cyclopropylphenyl)ethoxy]benzamideExemplary Compound No. 1-246

The same reaction as in Example 9 (9c) was conducted usingN-{4-[2-(4-cyclopropylphenyl)ethoxy]benzoyl}glycine (150 mg) prepared inExample 84 (84c) and 4-chlorobenzaldehyde (65 mg) to give thecorresponding oxazolone (112 mg). Then, the same reaction as in Example9 (9d) was conducted using 109 mg of this oxazolone to give 90 mg of thetitle compound (white amorphous solid).

MS (FAB) m/z: 506 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.72 (1H, brs), 8.03 (1H, t, J=6 Hz), 7.91 (2H, d, J=9 Hz), 7.50 (2H, d,J=9 Hz), 7.37 (2H, d, J=9 Hz), 7.18 (2H, d, J=8 Hz), 7.12 (1H, s), 7.01(2H, d, J=9 Hz), 7.00 (2H, d, J=8 Hz), 4.62 (1H, t, J=5 Hz), 4.22 (2H,t, J=7 Hz), 3.43 (2H, q, J=6 Hz), 3.22 (2H, q, J=6 Hz), 3.00 (2H, t, J=7Hz), 1.91-1.84 (1H, m), 0.94-0.89 (2H, m), 0.65-0.61 (2H, m).

Example 864-{2-[3-(Dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamideExemplary Compound No. 1-183

(86a) N-(4-{2-[3-(Dimethylamino)phenyl]ethoxy}benzoyl)glycine

The same reaction as in Example 78 (78a) was conducted usingN-(4-hydroxybenzoyl)glycine ethyl ester (which is the compound disclosedin J. Med. Chem., (1999), 42, 1041-1052, 666 mg, 2.98 mmol) and2-[3-(dimethylamino)phenyl]ethanol (555 mg, 3.36 mmol) to give 783 mg ofthe title compound (white powder, yield: 77%).

(86b)4-{2-[3-(Dimethylamino)phenyl]ethoxy}-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide

The same reaction as in Example 1 (1c) was conducted usingN-(4-{2-[3-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (242 mg)prepared in Example 86 (86a) and 4-(trifluoromethoxy)benzaldehyde (110μL) to give the corresponding oxazolone (245 mg). The same reaction asin Example 1 (1d) was conducted using all this oxazolone to give 192 mgof the title compound (white amorphous solid).

MS (FAB) m/z: 558 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.76 (1H, s), 8.05 (1H, brt, J=6 Hz), 7.92 (2H, d, J=9 Hz), 7.62 (2H, d,J=9 Hz), 7.31 (2H, d, J=8 Hz), 7.14 (1H, s), 7.09 (1H, t, J=8 Hz), 7.03(2H, d, J=9 Hz), 6.68 (1H, brs), 6.60 (1H, d, =7 Hz), 6.57 (1H, dd, J=8Hz, 2 Hz), 4.62 (1H, t, J=5 Hz), 4.25 (2H, t, J=7 Hz), 3.44 (2H, q, J=6Hz), 3.22 (2H, q, J=6 Hz), 2.98 (2H, t, J=7 Hz), 2.88 (6H, s).

Example 87N-((Z)-2-(4-Cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[3-(dimethylamino)phenyl]ethoxy}benzamideExemplary Compound No. 1-189

The same reaction as in Example 1 (1c) was conducted usingN-(4-{2-[3-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (242 mg)prepared in Example 86 (86a) and 4-cyclopropylbenzaldehyde (126 mg)prepared in Example 5 to give the corresponding oxazolone (222 mg). Thesame reaction as in Example 1 (1d) was conducted using all thisoxazolone to give 145 mg of the title compound (light yellow amorphoussolid).

MS (FAB) m/z: 514 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.69 (1H, s), 7.97-7.93 (3H, m), 7.41 (2H, d, J=8 Hz), 7.17 (1H, s),7.12 (1H, t, J=8 Hz), 7.05 (2H, d, J=9 Hz), 7.02 (2H, d, J=8 Hz), 6.70(1H, brs), 6.63 (1H, d, J=7 Hz), 6.60 (1H, dd, J=8 Hz, 2 Hz), 4.62 (1H,t, J=5 Hz), 4.27 (2H, t, J=7 Hz), 3.43 (2H, q, J=6 Hz), 3.22 (2H, q, J=6Hz), 3.00 (2H, t, J=7 Hz), 2.89 (6H, s), 1.90-1.84 (1H, m), 0.95-0.91(2H, m), 0.67-0.64 (2H, m).

Example 88N-((Z)-2-(4-Chlorophenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-{2-[3-(dimethylamino)phenyl]ethoxy}benzamideExemplary Compound No. 1-95

The same reaction as in Example 1 (1c) was conducted usingN-(4-{2-[3-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (241 mg)prepared in Example 86 (86a) and 4-chlorobenzaldehyde (108 mg) to givethe corresponding oxazolone (227 mg). Then, the same reaction as inExample 1 (1d) was conducted using all this oxazolone to give 160 mg ofthe title compound (white amorphous solid).

MS (FAB) m/z: 508 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.72 (1H, s), 8.03 (1H, brt, J=6 Hz), 7.91 (2H, d, J=9 Hz), 7.50 (2H, d,J=9 Hz), 7.37 (2H, d, J=9 Hz), 7.11 (1H, s), 7.09 (1H, t, J=7 Hz), 7.03(2H, d, J=9 Hz), 6.67 (1H, brs), 6.60 (1H, d, J=7 Hz), 6.57 (1H, dd, J=8Hz, 2 Hz), 4.62 (1H, t, J=6 Hz), 4.25 (2H, t, J=7 Hz), 3.43 (2H, q, J=6Hz), 3.22 (2H, q, J=6 Hz), 2.98 (2H, t, J=7 Hz), 2.87 (6H, s).

Example 894-(4-Ethylphenoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamideExemplary Compound No. 1-335

(89a) N-[4-(4-Ethylphenoxy)benzoyl]glycine

An oxidation reaction (which is the method disclosed in Tetrahedron,(1987), 43, 4767-4776) was conducted using4-(4-ethylphenoxy)benzaldehyde (which is the compound disclosed in J.Med. Chem., (1996), 39, 3984-3997, 500 mg, 2.21 mmol). 2-Methyl-2-butene(940 μL, 8.84 mmol), sodium dihydrogen phosphate dihydrate (338 mg, 2.16mmol), and sodium chlorite (80%, 875 mg, 7.74 mmol) were added to amixture solution of tert-butanol (3.6 mL) and water (1.0 mL) containing4-(4-ethylphenoxy)benzaldehyde. The resulting mixture was stirred atroom temperature, and the reaction was terminated with 1 N hydrochloricacid. After the extraction with ethyl acetate, the organic layer waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated to give 622 mg of 4-(4-ethylphenoxy)benzoic acid(white powder, yield: quantitative). Then, the same reaction as inExample 9 (9b) was conducted using all this 4-(4-ethylphenoxy)benzoicacid to give 437 mg of the title compound (pale red powder, yield: 66%).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

12.54 (1H, brs), 8.73 (1H, brt, J=6 Hz), 7.85 (2H, d, J=9 Hz), 7.25 (2H,d, J=9 Hz), 7.01 (2H, d, J=9 Hz), 6.97 (2H, d, J=9 Hz), 3.90 (2H, d, J=6Hz), 2.61 (2H, q, J=7 Hz), 1.19 (3H, t, J=7 Hz).

(89b)(4Z)-2-[4-(4-Ethylphenoxy)phenyl]-4-(4-isopropoxybenzylidene)-1,3-oxazol-5(4H)-one

A mixture of N-[4-(4-ethylphenoxy)benzoyl]glycine (200 mg, 0.668 mmol)prepared in Example 89 (89a) and acetic anhydride (0.38 mL, 4.03 mmol)was stirred at 80° C. for 20 minutes. Ethyl acetate was added to thereaction mixture, and then the mixture was cooled to room temperature.The solvent was evaporated, and then the residue was purified by silicagel column chromatography (hexane:ethyl acetate, 3:1, v/v) to give2-[4-(4-ethylphenoxy)phenyl]-1,3-oxazol-5(4H)-one (120 mg, 0.427 mmol).All of this 2-[4-(4-ethylphenoxy)phenyl]-1,3-oxazol-5(4H)-one wasdissolved in benzene (0.9 mL), and then 4-isopropoxybenzaldehyde (71 mg,0.432 mmol) and triethylamine (24 μL, 0.172 nmol) were added thereto.The mixture was stirred at 90° C. for 2 hours. After the addition ofwater to the reaction solution, the mixture was extracted with a solventmixture of hexane and ethyl acetate. The organic layers were combined,washed with saturated brine, dried over anhydrous sodium sulfate, andthen concentrated to give 181 mg of the title compound (brown oil,yield: 99%).

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.13 (2H, d, J=9 Hz), 8.08 (2H, d, J=9 Hz), 7.22 (2H, d, J=9 Hz), 7.15(1H, s), 7.03 (2H, d, J=9 Hz), 7.00 (2H, d, J=9 Hz), 6.94 (2H, d, J=9Hz), 4.69-4.62 (1H, m), 2.67 (2H, q, J=7 Hz), 1.38 (6H, d, J=6 Hz), 1.27(3H, t, J=7 Hz).

(89c)4-(4-Ethylphenoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

The same reaction as in Example 9 (9d) was conducted using(4Z)-2-[4-(4-ethylphenoxy)phenyl]-4-(4-isopropoxybenzylidene)-1,3-oxazol-5(4H)-one(181 mg, 0.422 mmol) prepared in Example 89 (89b) to give 115 mg of thetitle compound (light yellow amorphous solid, yield: 56%).

MS (FAB) m/z: 489 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.73 (1H, brs), 8.00 (2H, d, J=9 Hz), 7.89 (1H, t, J=5 Hz), 7.46 (2H, d,J=9 Hz), 7.27 (2H, d, J=8 Hz), 7.18 (1H, s), 7.02 (2H, d, J=9 Hz), 7.01(2H, d, J=8 Hz), 6.86 (2H, d, J=9 Hz), 4.64-4.58 (2H, m), 3.43 (2H, q,J=6 Hz), 3.22 (2H, q, J=6 Hz), 2.62 (2H, q, J=7 Hz), 1.23 (6H, d, J=6Hz), 1.20 (3H, t, J=8 Hz).

Example 90N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(4-phenylbutoxy)benzamideExemplary Compound No. 1-307

(90a) N-[4-(4-Phenylbutoxy)benzoyl]glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (249 mg, 0.991 mmol)prepared in Example 1 (1a) and 4-phenylbutan-1-ol (200 μL, 1.30 mmol) togive 203 mg of the title compound (white powder, yield: 63%).

(90b)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(4-phenylbutoxy)benzamide

The same reaction as in Example 1 (1c) was conducted usingN-[4-(4-phenylbutoxy)benzoyl]glycine (203 mg) prepared in Example 90(90a) and 4-isopropoxybenzaldehyde (108 μL) to give the correspondingoxazolone (167 mg). Then, the same reaction as in Example 1 (1d) wasconducted using all this oxazolone to give 110 mg of the title compound(white amorphous solid).

MS (FAB) m/z: 517 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.63 (1H, s), 7.94 (2H, d, J=9 Hz), 7.86 (1H, brt, J=6 Hz), 7.45 (2H, d,J=9 Hz), 7.29-7.25 (2H, m), 7.21-7.14 (4H, m), 7.01 (2H, d, J=9 Hz),6.84 (2H, d, J=9 Hz), 4.63-4.57 (2H, m), 4.07 (2H, t, J=5 Hz), 3.42 (2H,q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 2.65 (2H, t, J=7 Hz), 1.77-1.71 (4H,m), 1.22 (6H, d, J=6 Hz).

Example 91N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(3-phenylpropoxy)benzamideExemplary Compound No. 1-301

(91a) N-(4-Hydroxybenzoyl)glycine methyl ester

Oxazolyl chloride (4.0 mL, 45.9 mmol) and several drops of DMF wereadded to a solution of dichloromethane (5 mL) containing4-benzyloxybenzoic acid (2.29 g, 10.0 mmol) under ice-cooling, and thendichloromethane (2.5 mL) was further added thereto. The mixture wasstirred at room temperature for 2.5 hours, and the solvent wasevaporated. The resulting residue was dissolved in dichloromethane (20mL), and glycine methyl ester hydrochloride (1.39 g, 11.1 mmol) andN-ethyl-N,N-diisopropylamine (4.4 mL, 25.2 mmol) were added theretounder ice-cooling. The mixture was stirred at room temperature for 18hours, and then water was added thereto to terminate the reaction. Themixture was extracted with dichloromethane, and the organic layers werecombined and concentrated. The resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate, 3:4 to 0:1, v/v) togive N-[4-(benzyloxy)benzoyl]glycine methyl ester. Then, 1.66 g of thisester was dissolved in a solvent mixture of methanol (8 mL) and THF (8mL). To the resulting mixture, 20% palladium hydroxide-carbon (168 mg)was added. The mixture was vigorously stirred at room temperature undera hydrogen atmosphere for 4 hours. The reaction mixture was filteredthrough Celite and then concentrated to give 1.19 g of the titlecompound (white powder, yield: 85%).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

10.0 (1H, s), 8.65 (1H, brt, J=6 Hz), 7.71 (2H, d, J=9 Hz), 6.79 (2H, d,J=9 Hz), 3.95 (2H, d, J=6 Hz), 3.63 (3H, s).

(91b) N-[4-(3-Phenylpropoxy)benzoyl]glycine

N-(4-Hydroxybenzoyl)glycine methyl ester (0.34 g, 1.63 mmol) prepared inExample 91 (91a), 3-phenylpropan-1-ol (0.23 mL, 1.70 mmol), andtriphenylphosphine (457 mg, 1.74 mmol) were dissolved in THF (6.5 mL),and diethyl azodicarboxylate (0.88 mL, 40% toluene solution, 1.76 mmol)was added thereto while stirring under ice-cooling. The resultingmixture was stirred at room temperature for 3.5 hours, and then thereaction solution was diluted with ethyl acetate, washed with water andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated, and the resulting residue was purified by silica gelcolumn chromatography (hexane to hexane:ethyl acetate, 5:1, 3:1, 2:1,and 1:1, v/v) to give 490 mg of an oily substance.

All this oily substance was dissolved in ethanol (7.5 mL), and a 2 Nsodium hydroxide aqueous solution (3.80 mL, 7.60 mmol) was addedthereto. The mixture was stirred at 90° C. for 2 hours and then cooledwith ice. This mixture was made acidic with concentrated hydrochloricacid and then concentrated. After the evaporation of ethanol, theresulting precipitate was collected by filtration, washed with water,and dried by heating under reduced pressure to give 318 mg of the titlecompound (yield: 63%).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

12.6 (1H, brs), 8.67 (1H, brt, J=6 Hz), 7.83 (2H, d, J=9 Hz), 7.30-7.17(5H, m), 7.01 (2H, d, J=9 Hz), 4.03 (2H, t, J=7 Hz), 3.90 (2H, d, J=6Hz), 2.75 (2H, t, J=7 Hz), 2.06-2.01 (2H, m).

(91c)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(3-phenylpropoxy)benzamide

The same reaction as in Example 1 (1c) was conducted usingN-[4-(3-phenylpropoxy)benzoyl]glycine (227 mg) prepared in Example 91(91b) and 4-isopropoxybenzaldehyde (125 μL) to give the correspondingoxazolone (244 mg). Then, the same reaction as in Example 1 (1d) wasconducted using all this oxazolone to give 130 mg of the title compound(white amorphous solid).

MS (FAB) m/z: 503 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.64 (1H, s), 7.95 (2H, d, J=9 Hz), 7.86 (1H, brt, J=5 Hz), 7.45 (2H, d,J=9 Hz), 7.29-7.17 (5H, m), 7.16 (1H, s), 7.02 (2H, d, J=9 Hz), 6.84(2H, d, J=9 Hz), 4.63-4.57 (2H, m), 4.04 (2H, t, J=6 Hz), 3.42 (2H, q,J=6 Hz), 3.21 (2H, q, J=6 Hz), 2.75 (2H, t, J=7 Hz), 2.08-2.01 (2H, m),1.23 (6H, d, J=6 Hz).

Example 924-(2,3-Dihydro-1H-inden-2-ylmethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamideExemplary Compound No. 1-341

(92a) N-[4-(2,3-Dihydro-1H-inden-2-ylmethoxy)benzoyl]glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (250 mg, 0.995 mmol)prepared in Example 1 (1a) and 2,3-dihydro-1H-inden-2-ylmethanol (whichis the compound disclosed in J. Med. Chem., (1989), 32, 1326-1334, 165mg, 1.11 mmol) to give 263 mg of the title compound (colorlesscrystalline solid, yield: 85%).

(92b)4-(2,3-Dihydro-1H-inden-2-ylmethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

The same reaction as in Example 1 (1c) was conducted usingN-[4-(2,3-dihydro-1H-inden-2-ylmethoxy)benzoyl]glycine (258 mg) preparedin Example 92 (92a) and 4-isopropoxybenzaldehyde (138 μL) to give thecorresponding oxazolone (279 mg). Then, the same reaction as in Example1 (1d) was conducted using all this oxazolone to give 130 mg of thetitle compound (white amorphous solid).

MS (FAB) m/z: 515 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.68 (1H, s), 7.98 (2H, d, J=9 Hz), 7.89 (1H, brt, J=5 Hz), 7.47 (2H, d,J=9 Hz), 7.26-7.24 (2H, m), 7.18 (1H, s), 7.15-7.12 (2H, m), 7.08 (2H,d, J=9 Hz), 6.86 (2H, d, J=9 Hz), 4.64-4.59 (2H, m), 4.08 (2H, d, J=7Hz), 3.43 (2H, q, J=6 Hz), 3.22 (2H, q, J=6 Hz), 3.11 (2H, dd, J=16 Hz,8 Hz), 2.94 (1H, sept, J=7 Hz), 2.81 (2H, dd, J=16 Hz, 7 Hz), 1.23 (6H,d, J=6 Hz).

Example 934-(2-Cyclopenta-2-en-1-ylethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamideExemplary Compound No. 1-344

(93a) N-[4-(2-Cyclopenta-2-en-1-ylethoxy)benzoyl]glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (157 mg, 0.625 mmol)prepared in Example 1 (1a) and 2-cyclopenta-2-en-1-ylethanol (which isthe compound disclosed in J. Org. Chem., (2000), 65, 4241-4250, 85 mg,0.75 mmol) to give 128 mg of the title compound (white powder, yield:72%).

(93b)4-(2-Cyclopenta-2-en-1-ylethoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

The same reaction as in Example 1 (1c) was conducted usingN-[4-(2-cyclopenta-2-en-1-ylethoxy)benzoyl]glycine (128 mg) prepared inExample 93 (93a) and 4-isopropoxybenzaldehyde (76 mg) to give thecorresponding oxazolone (90 mg). Then, the same reaction as in Example 1(1d) was conducted using 75 mg of this oxazolone to give 77 mg of thetitle compound (white powder).

mp: 67 to 70° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.94 (1H, brs), 7.82 (2H, d, J=9 Hz), 7.32 (2H, d, J=9 Hz), 7.04 (1H,s), 6.91 (2H, d, J=9 Hz), 6.83 (1H, t, J=5 Hz), 6.80 (2H, d, J=9 Hz),5.80-5.76 (1H, m), 5.74-5.71 (1H, m), 4.52 (1H, sept, J=6 Hz), 4.05 (2H,t, J=6 Hz), 3.73 (2H, t, J=5 Hz), 3.45 (2H, q, J=5 Hz), 3.33 (1H, brs),2.88 (1H, brt, J=6 Hz), 2.43-2.26 (2H, m), 2.17-2.07 (1H, m), 1.92 (1H,sept, J=7 Hz), 1.80 (1H, sept, J=7 Hz), 1.54-1.45 (1H, m), 1.32 (6H, d,J=6 Hz).

Example 94N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenylpropoxy)benzamideExemplary Compound No. 1-347

(94a) N-[4-(2-Phenylpropoxy)benzoyl]glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (247 mg, 0.983 mmol)prepared in Example 1 (1a) and 2-phenylpropan-1-ol (185 μL, 1.32 mmol)to give 221 mg of the title compound (white powder, yield: 72%).

(94b)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-(2-phenylpropoxy)benzamide

The same reaction as in Example 1 (1c) was conducted usingN-[4-(2-phenylpropoxy)benzoyl]glycine (219 mg) prepared in Example 94(94a) and 4-isopropoxybenzaldehyde (121 μL) to give the correspondingoxazolone (185 mg). Then, the same reaction as in Example 1 (1d) wasconducted using all this oxazolone to give 134 mg of the title compound(white amorphous solid).

MS (FAB) m/z: 503 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.63 (1H, s), 7.93 (2H, d, J=9 Hz), 7.85 (1H, brt, J=6 Hz), 7.44 (2H, d,J=9 Hz), 7.35-7.29 (4H, m), 7.23-7.20 (1H, m), 7.15 (1H, s), 7.01 (2H,d, J=9 Hz), 6.83 (2H, d, J=9 Hz), 4.63-4.57 (2H, m), 4.21-4.10 (2H, m),3.41 (2H, q, J=6 Hz), 3.25-3.18 (3H, m), 1.33 (3H, d, J=7 Hz), 1.22 (6H,d, J=6 Hz).

Example 954-(4-Cyclopropylbutoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamideExemplary Compound No. 1-350

(95a) N-[4-(4-Cyclopropylbutoxy)benzoyl]glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (251 mg, 1.00 mmol)prepared in Example 1 (1a) and 4-cyclopropylbutan-1-ol (which is thecompound disclosed in J. Med. Chem., (1998), 41, 1112-1123, 137 mg, 1.20mmol) to give 257 mg of the title compound (white powder, yield: 88%).

(95b)4-(4-Cyclopropylbutoxy)-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

The same reaction as in Example 1 (1c) was conducted usingN-[4-(4-cyclopropylbutoxy)benzoyl]glycine (146 mg) prepared in Example95 (95a) and 4-isopropoxybenzaldehyde (86 mg) to give the correspondingoxazolone (94 mg). Then, the same reaction as in Example 1 (1d) wasconducted using all this oxazolone to give 55 mg of the title compound(white powder).

mp: 53 to 55° C.;

¹H-nuclear magnetic resonance spectrum (500 MHz, CDCl₃) δ ppm:

8.14 (1H, brs), 7.81 (2H, d, J=9 Hz), 7.30 (2H, d, J=9 Hz), 6.99 (1H,s), 6.97 (1H, t, J=5 Hz), 6.88 (2H, d, J=9 Hz), 6.77 (2H, d, J=9 Hz),4.51 (1H, sept, J=6 Hz), 3.98 (2H, t, J=6 Hz), 3.68 (2H, t, J=5 Hz),3.40 (2H, q, J=5 Hz), 1.88-1.77 (2H, m), 1.62-1.51 (2H, m), 1.31 (6H, d,J=6 Hz), 1.32-1.26 (2H, m), 0.73-0.65 (1H, m), 0.45-0.41 (2H, m),0.05-0.02 (2H, m).

Example 96N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(2-naphthyl)ethoxy]benzamideExemplary Compound No. 1-353

(96a) N-{4-[2-(2-Naphthyl)ethoxy]benzoyl}glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (251 mg, 1.00 mmol)prepared in Example 1 (1a) and 2-(2-naphthyl)ethanol (207 mg, 1.20 mmol)to give 314 mg of the title compound (white powder, yield: 90%).

(96b)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(2-naphthyl)ethoxy]benzamide

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(2-naphthyl)ethoxy]benzoyl}glycine (140 mg) prepared in Example96 (96a) and 4-isopropoxybenzaldehyde (69 mg) to give the correspondingoxazolone (108 mg). Then, the same reaction as in Example 1 (1d) wasconducted using 81 mg of this oxazolone to give 57 mg of the titlecompound (white powder).

mp: 78 to 79° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.03 (1H, brs), 7.82-7.75 (5H, m), 7.69 (1H, s), 7.47-7.37 (3H, m), 7.27(2H, d, J=9 Hz), 6.97 (1H, s), 6.88-6.86 (3H, m), 6.74 (2H, d, J=9 Hz),4.47 (1H, sept, J=6 Hz), 4.26 (2H, t, J=6 Hz), 3.67 (2H, t, J=5 Hz),3.39 (2H, q, J=5 Hz), 3.25 (2H, t, J=6 Hz), 1.28 (6H, d, J=6 Hz).

Example 97N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-{2-[3-(trifluoromethyl)phenyl]ethoxy}benzamideExemplary Compound No. 1-356

(97a) N-(4-{2-[3-(Trifluoromethyl)phenyl]ethoxy}benzoyl)glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (502 mg, 2.00 mmol)prepared in Example 1 (1a) and 2-[3-(trifluoromethyl)phenyl]ethanol (330μL, 2.20 mmol) to give 368 mg of the title compound (white powder,yield: 80%).

(97b)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-{2-[3-(trifluoromethyl)phenyl]ethoxy}benzamide

The same reaction as in Example 1 (I c) was conducted usingN-(4-{2-[3-(trifluoromethyl)phenyl]ethoxy}benzoyl)glycine (368 mg)prepared in Example 97 (97a) and 4-isopropoxybenzaldehyde (174 μL) togive the corresponding oxazolone (338 mg). The same reaction as inExample 1 (1d) was conducted using all this oxazolone to give 311 mg ofthe title compound (white amorphous solid).

MS (FAB) m/z: 557 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.68 (1H, s), 7.98 (2H, d, J=7 Hz), 7.89 (1H, brt, J=5 Hz), 7.74 (1H,s), 7.68 (1H, d, J=7 Hz), 7.62-7.55 (2H, m), 7.47 (2H, d, J=9 Hz), 7.18(1H, s), 7.06 (2H, d, J=8 Hz), 6.86 (2H, d, J=8 Hz), 4.64-4.58 (2H, m),4.34 (2H, d, J=6 Hz), 3.43 (2H, q, J=6 Hz), 3.24-3.17 (4H, m), 1.23 (6H,d, J=6 Hz).

Example 984-[2-(2-Fluorophenyl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamideExemplary Compound No. 1-359

(98a) N-{4-[2-(2-Fluorophenyl)ethoxy]benzoyl}glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (231 mg, 0.919 mmol)prepared in Example 1 (1a) and 2-(2-fluorophenyl)ethanol (137 μL, 1.02mmol) to give 214 mg of the title compound (white powder, yield: 73%).

(98b)4-[2-(2-Fluorophenyl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(2-fluorophenyl)ethoxy]benzoyl}glycine (214 mg) prepared inExample 98 (98a) and 4-isopropoxybenzaldehyde (118 μL) to give thecorresponding oxazolone (232 mg). The same reaction as in Example 1 (1d)was conducted using all this oxazolone to give 168 mg of the titlecompound (white amorphous solid).

MS (FAB) m/z: 507 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.68 (1H, s), 7.98 (2H, d, J=8 Hz), 7.90 (1H, brt, J=5 Hz), 7.48-7.42(3H, m), 7.34-7.29 (1H, m), 7.22-7.16 (3H, m), 7.05 (2H, d, J=8 Hz),6.86 (2H, d, J=8 Hz), 4.64-4.59 (2H, m), 4.29 (2H, t, J=7 Hz), 3.43 (2H,q, J=6 Hz), 3.22 (2H, q, J=6 Hz), 3.11 (2H, t, J=7 Hz), 1.23 (6H, d, J=6Hz).

Example 994-[2-(4-Cyanophenyl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamideExemplary Compound No. 1-362

(99a) N-{4-[2-(4-Cyanophenyl)ethoxy]benzoyl}glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (582 mg, 3.83 mmol)prepared in Example 1 (1a) and 4-(2-hydroxyethyl)benzonitrile (592 mg,4.02 mmol) to give 226 mg of the title compound (white powder, yield:46%).

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

12.5 (1H, s), 8.65 (1H, t, J=9 Hz), 7.80 (2H, d, J=9 Hz), 7.77 (2H, d,J=9 Hz), 7.53 (2H, d, J=9 Hz), 6.98 (2H, d, J=9 Hz), 4.29 (2H, t, J=7Hz), 3.87 (2H, d, J=6 Hz), 3.15 (2H, t, J=7 Hz).

(99b)4-[2-(4-Cyanophenyl)ethoxy]-N-[(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]benzamide

The same reaction as in Example 1 (1c) was conducted usingN-{4-[2-(4-cyanophenyl)ethoxy]benzoyl}glycine (226 mg) prepared inExample 99 (99a) and 4-isopropoxybenzaldehyde (121 μL) to give thecorresponding oxazolone (217 mg). Then, the same reaction as in Example1 (1d) was conducted using all this oxazolone to give 128 mg of thetitle compound (white amorphous solid).

MS (FAB) m/z: 514 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.65 (1H, s), 7.95 (2H, d, J=9 Hz), 7.87 (1H, brt, J=5 Hz), 7.78 (2H, d,J=8 Hz), 7.55 (2H, d, J=8 Hz), 7.44 (2H, d, J=9 Hz), 7.16 (1H, s), 7.02(2H, d, J=9 Hz), 6.83 (2H, d, J=9 Hz), 4.63-4.57 (2H, m), 4.32 (2H, t,J=7 Hz), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 3.16 (2H, t, J=7Hz), 1.22 (6H, d, J=6 Hz).

Example 100N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-{2-[4-(trifluoromethyl)phenyl]ethoxy}benzamideExemplary Compound No. 1-365

(100a) N-(4-{2-[4-(Trifluoromethyl)phenyl]ethoxy}benzoyl)glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (251 mg, 1.00 mmol)prepared in Example 1 (1a) and 2-[4-(trifluoromethyl)phenyl]ethanol (209mg, 1.10 mmol) prepared according to the method disclosed in thedocument (J. Med. Chem., (2002), 45, 4321-4335) to give 278 mg of thetitle compound (white powder, yield: quantitative).

(100b)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-{2-[4-(trifluoromethyl)phenyl]ethoxy}benzamide

The same reaction as in Example 1 (1c) was conducted usingN-(4-{2-[4-(trifluoromethyl)phenyl]ethoxy}benzoyl)glycine (278 mg)prepared in Example 100 (100a) and 4-isopropoxybenzaldehyde (130 mg) togive the corresponding oxazolone (180 mg). Then, the same reaction as inExample 1 (1d) was conducted using all this oxazolone to give 28 mg ofthe title compound (white amorphous solid).

MS (FAB) m/z: 557 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

7.79 (3H, brd, J=9 Hz), 7.57 (2H, d, J=8 Hz), 7.39 (2H, d, J=8 Hz), 7.30(2H, d, J=9 Hz), 7.03 (1H, s), 6.89 (2H, d, J=9 Hz), 6.78 (2H, d, J=9Hz), 6.72-6.68 (1H, m), 4.51 (1H, sept, J=6 Hz), 4.23 (2H, t, J=7 Hz),3.74 (2H, brs), 3.46 (2H, q, J=5 Hz), 3.17 (3H, brt, J=7 Hz), 1.31 (6H,d, J=6 Hz).

Example 101N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-methylphenyl)ethoxy]benzamideExemplary Compound No. 1-368

(101a) N-{4-[2-(4-Methylphenyl)ethoxy]benzoyl}glycine

The same reaction as in Example 1 (1b) was conducted usingN-(4-hydroxybenzoyl)glycine tert-butyl ester (275 mg, 1.09 mmol)prepared in Example 1 (1a) and 2-(4-methylphenyl)ethanol (159 μL, 1.14mmol) to give 306 mg of the title compound (colorless crystalline solid,yield: 90%).

(101b)N-[(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-[2-(4-methylphenyl)ethoxy]benzamide

The same reaction as in Example 1 (I c) was conducted usingN-{4-[2-(4-methylphenyl)ethoxy]benzoyl}glycine (306 mg) prepared inExample 101 (101a) and 4-isopropoxybenzaldehyde (176 mg) to give thecorresponding oxazolone (335 mg). Then, the same reaction as in Example1 (1d) was conducted using all this oxazolone to give 300 mg of thetitle compound (light yellow amorphous solid).

MS (FAB) m/z: 503 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.63 (1H, brs), 7.94 (2H, d, J=9 Hz), 7.86 (1H, brt, J=5 Hz), 7.44 (2H,d, J=9 Hz), 7.20 (2H, d, J=8 Hz), 7.15 (1H, s), 7.11 (2H, d, J=8 Hz),7.02 (2H, d, J=9 Hz), 6.84 (2H, d, J=9 Hz), 4.63-4.57 (2H, m), 4.24 (2H,t, J=7 Hz), 3.42 (2H, q, J=6 Hz), 3.21 (2H, q, J=6 Hz), 3.01 (2H, t, J=7Hz), 2.27 (3H, s), 1.22 (6H, d, J=6 Hz).

Example 102N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[2-(4-isopropoxyphenyl)ethoxy]benzamideExemplary Compound No. 1-373

(102a) N-{4-[2-(4-Isopropoxyphenyl)ethoxy]benzoyl}glycine

The same reaction as in Example 78 (78a) was conducted usingN-(4-hydroxybenzoyl)glycine ethyl ester (which is the compound disclosedin J. Med. Chem., (1999), 42, 1041-1052, 397 mg, 2.20 mmol) and2-(4-isopropoxyphenyl)ethanol (which is the compound disclosed in J.Chem. Soc. Perkin Trans. 1, (1983), 619-624, 447 mg, 2.00 mmol) to give636 mg of the title compound (white powder, yield: 82%).

(102b)N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[2-(4-isopropoxyphenyl)ethoxy]benzamide

The same reaction as in Example 1 (I c) was conducted usingN-{4-[2-(4-isopropoxyphenyl)ethoxy]benzoyl}glycine (228 mg) prepared inExample 102 (102a) and 4-(trifluoromethoxy)benzaldehyde (96 μL) to givethe corresponding oxazolone (207 mg). Then, the same reaction as inExample 1 (1d) was conducted using 204 mg of this oxazolone to give 171mg of the title compound (white amorphous solid).

MS (FAB) m/z: 573 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.76 (1H, brs), 8.05 (1H, t, J=6 Hz), 7.92 (2H, d, J=9 Hz), 7.62 (2H, d,J=9 Hz), 7.31 (2H, d, J=8 Hz), 7.20 (2H, d, J=9 Hz), 7.14 (1H, s), 7.02(2H, d, J=9 Hz), 6.83 (2H, d, J=9 Hz), 4.62 (1H, t, J=5 Hz), 4.55 (1H,sept, J=6 Hz), 4.22 (2H, t, J=7 Hz), 3.44 (2H, q, J=6 Hz), 3.22 (2H, q,J=6 Hz), 2.98 (2H, t, J=7 Hz), 1.24 (6H, d, J=6 Hz).

Example 103N-[(E)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-isobutoxybenzamide

(103a)2-(4-Isobutoxyphenyl)-4-(4-isopropoxybenzylidene)-1,3-oxazol-5(4H)-one

The same reaction as in Example 1 (1c) was conducted usingN-(4-isobutoxybenzoyl)glycine (5.00 g) prepared in Example 30 (30a) and4-isopropoxybenzaldehyde (3.59 g) to give the corresponding oxazolone(4.21 g). Then, 313 mg of this oxazolone was dissolved in a 33% hydrogenbromide-acetic acid solution (5.0 mL) at room temperature. The resultingsolution was stirred for 0.5 hours and then poured in ice water. Theprecipitated crystals were collected by filtration, washed with water,and dried to give 282 mg of the title compound (yellow powder, yield:84%, a mixture of 4E isomer/4Z isomer=4.6/1).

MS (FAB) m/z: 380 [M+H]⁺;

4E isomer: ¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δppm: 8.18 (2H, d, J=9 Hz), 7.99 (2H, d, J=9 Hz), 7.45 (1H, s), 6.99 (2H,d, J=9 Hz), 6.95 (2H, d, J=9 Hz), 4.66 (1H, quint, J=6 Hz), 3.80 (2H, d,J=6 Hz), 2.12 (1H, sept, J=6 Hz), 1.38 (6H, d, J=5 Hz), 1.05 (6H, d, J=7Hz).

(103b)N-[(E)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-(4-isopropoxyphenyl)vinyl]-4-isobutoxybenzamide

2-Aminoethanol (50 μL, 0.828 mmol) was added to a solution of toluene(2.0 mL) containing2-(4-isobutoxyphenyl)-4-(4-isopropoxybenzylidene)-1,3-oxazol-5(4H)-one(151 mg, 0.398 mmol, a mixture of 4E isomer/4Z isomer=4.6/1) prepared inExample 103 (103a). The mixture was stirred at 50° C. for 15 minutes,and then water was added to this reaction solution. The resultingmixture was extracted with ethyl acetate. The organic layers werecombined, washed with water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated, and theresulting residue was purified by thin layer chromatography forseparation (ethyl acetate) to give 37 mg of the title compound (whitesolid, yield: 21%). [In addition, 53 mg of the corresponding Z isomer ofthe title compound (white solid, yield: 30%) was given.]

MS (FAB) m/z: 441 [M+H]⁺;

¹H-nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:

8.50 (1H, s), 7.91 (1H, s), 7.82 (2H, d, J=9 Hz), 7.27 (2H, d, J=9 Hz),6.94 (2H, d, J=9 Hz), 6.88 (2H, d, J=9 Hz), 6.17 (1H, brt, J=6 Hz), 4.56(1H, sept, J=6 Hz), 3.77 (2H, d, J=7 Hz), 3.61 (2H, t, J=5 Hz), 3.36(2H, q, J=5 Hz), 2.11 (1H, sept, J=7 Hz), 1.35 (6H, d, J=6 Hz), 1.04(6H, d, J=7 Hz).

Example 1044-(Cyclopropylmethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamideExemplary Compound No. 1-440

The same reaction as in Example 9 (9c) was conducted usingN-[4-(cyclopropylmethoxy)benzoyl]glycine (499 mg) prepared by the samemethod as in Example 9 (9b) and 4-(trifluoromethoxy)benzaldehyde (300mL) to give the corresponding oxazolone (668 mg). The same reaction asin Example 9 (9d) was conducted using all this oxazolone to give 698 mgof the title compound (white powder).

mp: 144 to 145° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.77 (1H, brs), 8.06 (1H, t, J=6 Hz), 7.93 (2H, d, J=9 Hz), 7.63 (2H, d,J=9 Hz), 7.33 (2H, d, J=9 Hz), 7.16 (1H, s), 7.02 (2H, d, J=9 Hz), 4.63(1H, t, J=6 Hz), 3.90 (2H, d, J=7 Hz), 3.45 (2H, q, J=6 Hz), 3.23 (2H,q, J=6 Hz), 1.28-1.21 (1H, m), 0.61-0.57 (2H, m), 0.36-0.32 (2H, m).

Example 105N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[(1-methylcyclopropyl)methoxy]benzamideExemplary Compound No. 1-443

The same reaction as in Example 9 (9c) was conducted usingN-{4-[(1-methylcyclopropyl)methoxy]benzoyl}glycine (363 mg) prepared bythe same method as in Example 9 (9b) and4-(trifluoromethoxy)benzaldehyde (207 μL) to give the correspondingoxazolone (532 mg). Then, the same reaction as in Example 9 (9d) wasconducted using all this oxazolone to give 545 mg of the title compound(white powder).

mp: 170 to 173° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.77 (1H, brs), 8.06 (1H, t, J=6 Hz), 7.93 (2H, d, J=9 Hz), 7.63 (2H, d,J=9 Hz), 7.33 (2H, d, J=9 Hz), 7.15 (1H, s), 7.02 (2H, d, J=9 Hz), 4.63(1H, t, J=6 Hz), 3.84 (2H, s), 3.45 (2H, q, J=6 Hz), 3.23 (2H, q, J=6Hz), 1.19 (3H, s), 0.55-0.53 (2H, m), 0.42-0.40 (2H, m).

Example 106N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-isopropoxybenzamideExemplary Compound No. 1-415

The same reaction as in Example 9 (9c) was conducted usingN-(4-isopropoxybenzoyl)glycine (which is the compound disclosed inTetrahedron Lett., (1995), 36, 6193-6196, 380 mg) and4-(trifluoromethoxy)benzaldehyde (240 μL) to give the correspondingoxazolone (548 mg). Then, the same reaction as in Example 9 (9d) wasconducted using all this oxazolone to give 588 mg of the title compound(white powder).

mp: 142 to 146° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.77 (1H, brs), 8.05 (1H, t, J=6 Hz), 7.93 (2H, d, J=9 Hz), 7.64 (2H, d,J=9 Hz), 7.34 (2H, d, J=9 Hz), 7.16 (1H, s), 7.01 (2H, d, J=9 Hz), 4.74(1H, sept, J=6 Hz), 4.63 (1H, t, J=6 Hz), 3.44 (2H, q, J=6 Hz), 3.23(2H, q, J=6 Hz), 1.29 (6H, d, J=6 Hz).

Example 107N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(4,4,4-trifluorobutoxy)benzamideExemplary Compound No. 1-506

The same reaction as in Example 9 (9c) was conducted usingN-[4-(4,4,4-trifluorobutoxy)benzoyl]glycine (350 mg) prepared by thesame method as in Example 9 (9b) and 4-(trifluoromethoxy)benzaldehyde(172 μL) to give the corresponding oxazolone (337 mg). Then, the samereaction as in Example 9 (9d) was conducted using all this oxazolone togive 297 mg of the title compound (white powder).

mp: 160 to 163° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.79 (1H, brs), 8.06 (1H, t, J=6 Hz), 7.95 (2H, d, J=9 Hz), 7.64 (2H, d,J=9 Hz), 7.33 (2H, d, J=9 Hz), 7.19 (1H, s), 7.05 (2H, d, J=9 Hz), 4.63(1H, t, J=6 Hz), 4.13 (2H, t, J=6 Hz), 3.45 (2H, q, J=6 Hz), 3.23 (2H,q, J=6 Hz), 2.56-2.38 (2H, m), 2.00-1.93 (2H, m).

Example 108N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamideExemplary Compound No. 1-277

The same reaction as in Example 9 (9c) was conducted usingN-[4-(3,3,3-trifluoropropoxy)benzoyl]glycine (291 mg) prepared by thesame method as in Example 9 (9b) and 4-(trifluoromethoxy)benzaldehyde(150 μL) to give the corresponding oxazolone (390 mg). The same reactionas in Example 9 (9d) was conducted using all this oxazolone to give 349mg of the title compound (white powder).

mp: 159 to 160° C.;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.82 (1H, brs), 8.08 (1H, t, J=6 Hz), 7.97 (2H, d, J=9 Hz), 7.64 (2H, d,J=9 Hz), 7.34 (2H, d, J=9 Hz), 7.17 (1H, s), 7.08 (2H, d, J=9 Hz), 4.64(1H, t, J=6 Hz), 4.30 (2H, t, J=6 Hz), 3.45 (2H, q, J=6 Hz), 3.23 (2H,q, J=6 Hz), 2.87-2.78 (2H, m).

Example 109N-((Z)-2-[2-Fluoro-4-(trifluoromethyl)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(3,3,3-trifluoropropoxy)benzamide

The same reaction as in Example 9 (9c) was conducted usingN-[4-(3,3,3-trifluoropropoxy)benzoyl]glycine (300 mg) prepared by thesame method as in Example 9 (9b) and2-fluoro-4-trifluoromethylbenzaldehyde (150 μL) to give thecorresponding oxazolone (265 mg). The same reaction as in Example 9 (9d)was conducted using all this oxazolone to give 286 mg of the titlecompound (white powder).

mp: 203 to 205° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm: 9.83(1H, s), 8.26 (1H, t, J=5 Hz), 7.90 (2H, d, J=9 Hz), 7.71 (2H, d, J=9Hz), 7.54 (1H, d, J=8 Hz), 7.07 (2H, d, J=9 Hz), 7.06 (1H, s), 4.65 (1H,t, J=5 Hz), 4.29 (2H, t, J=6 Hz), 3.46 (2H, q, J=6 Hz), 3.25 (2H, q, J=6Hz), 2.88-2.77 (2H, m).

Example 110N-((Z)-2-[3-Fluoro-4-(trifluoromethyl)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(3,3,3-trifluoropropoxy)benzamide

The same reaction as in Example 9 (9c) was conducted usingN-[4-(3,3,3-trifluoropropoxy)benzoyl]glycine (300 mg) prepared by thesame method as in Example 9 (9b) and3-fluoro-4-trifluoromethylbenzaldehyde (208 mg) to give thecorresponding oxazolone (274 mg). Then, the same reaction as in Example9 (9d) was conducted using all this oxazolone to give 281 mg of thetitle compound (light yellow powder).

mp: 185 to 186° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.90 (1H, s), 8.23 (1H, t, J=6 Hz), 7.95 (2H, d, J=9 Hz), 7.76 (1H, t,J=8 Hz), 7.59 (1H, d, J=13 Hz), 7.52 (1H, d, J=8 Hz), 7.14 (1H, s), 7.09(2H, d, J=9 Hz), 4.65 (1H, t, J=6 Hz), 4.30 (2H, t, J=6 Hz), 3.45 (2H,q, J=6 Hz), 3.24 (2H, q, J=6 Hz), 2.89-2.77 (2H, m).

Example 111N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-propoxybenzamide

The same reaction as in Example 9 (9c) was conducted usingN-(4-propoxybenzoyl)glycine (which is the compound disclosed in Chem.Abstr., (1974), 80, 60167w, 403 mg) and 4-trifluoromethoxybenzaldehyde(255 μL) to give the corresponding oxazolone (461 mg). Then, the samereaction as in Example 9 (9d) was conducted using all this oxazolone togive 353 mg of the title compound (white amorphous solid).

mp: 185 to 186° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.79 (1H, s), 8.07 (1H, t, J=6 Hz), 7.95 (2H, d, J=9 Hz), 7.64 (2H, d,J=9 Hz), 7.34 (2H, d, J=9 Hz), 7.16 (1H, s), 7.03 (2H, d, J=9 Hz), 4.64(1H, t, J=6 Hz), 4.02 (2H, t, J=6 Hz), 3.44 (2H, q, J=6 Hz), 3.23 (2H,q, J=6 Hz), 1.80-1.71 (2H, m), 0.99 (3H, t, J=7 Hz).

Example 112N-{(Z)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamideExemplary Compound No. 1-519

The same reaction as in Example 9 (9c) was conducted usingN-{4-[4-(trifluoromethyl)phenoxy]benzoyl}glycine (382 mg) prepared bythe same method as in Example 9 (9b) and 4-trifluoromethoxybenzaldehyde(169 μL) to give the corresponding oxazolone (256 mg). The same reactionas in Example 9 (9d) was conducted using all this oxazolone to give 256mg of the title compound (white powder).

mp: 84 to 86° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.96 (1H, brs), 8.12 (1H, t, J=6 Hz), 8.06 (2H, d, J=9 Hz), 7.80 (2H, d,J=9 Hz), 7.66 (2H, d, J=9 Hz), 7.35 (2H, d, J=9 Hz), 7.26-7.19 (5H, m),4.64 (1H, t, J=6 Hz), 3.45 (2H, q, J=6 Hz), 3.24 (2H, q, J=6 Hz).

Example 1134-(4-Chlorophenoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide

The same reaction as in Example 9 (9c) was conducted usingN-[4-(4-chlorophenoxy)benzoyl]glycine (333 mg) prepared by the samemethod as in Example 9 (9b) and 4-trifluoromethoxybenzaldehyde (163 μL)to give the corresponding oxazolone (270 mg). The same reaction as inExample 9 (9d) was conducted using all this oxazolone to give 248 mg ofthe title compound (white powder).

mp: 77 to 82° C.;

¹H-nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:

9.91 (1H, brs), 8.09 (1H, t, J=6 Hz), 8.02 (2H, d, J=9 Hz), 7.65 (2H, d,J=9 Hz), 7.50 (2H, d, J=9 Hz), 7.35 (2H, d, J=9 Hz), 7.18 (1H, s), 7.13(2H, d, J=9 Hz), 7.11 (2H, d, J=9 Hz), 4.63 (1H, t, J=6 Hz), 3.45 (2H,q, J=6 Hz), 3.23 (2H, q, J=6 Hz).

Example 114N-{(Z)-1-{[(2,2-Difluoroethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}-4-(3,3,3-trifluoropropoxy)benzamide

The same reaction as in Example 9 (9d) was conducted using oxazolone(223 mg) prepared in the manufacturing process of Example 108 and2,2-difluoroethylamine (49 mg) to give 180 mg of the title compound(white powder).

mp: 142 to 143° C.;

¹H-nuclear magnetic resonance spectrum (500 MHz, DMSO-d₆) δ ppm:

9.89 (1H, s), 8.53 (1H, t, J=6 Hz), 7.98 (2H, d, J=9 Hz), 7.67 (2H, d,J=9 Hz), 7.36 (2H, d, J=9 Hz), 7.20 (1H, s), 7.09 (2H, d, J=9 Hz), 6.03(1H, tt, J=56 Hz, 4 Hz), 4.30 (2H, t, J=6 Hz), 3.59-3.51 (2H, m),2.87-2.78 (2H, m).

In addition to the above-mentioned Examples 1 to 114, compounds shown inTable 4 were also synthesized similarly. In Table 4, the same ExemplaryCompound Numbers as those in the above-mentioned Tables 1, 2, and 3denote the same compounds.

TABLE 4 Exemplary FABMS Compound No. State Melting point (° C.) ([M +H]⁺) 1-6 colorless crystalline solid 142-143 1-20 colorless crystallinesolid 76-80 1-21 colorless crystalline solid 85-89 1-22 colorlesscrystalline solid 198-200 1-23 colorless crystalline solid 183-185 1-24colorless crystalline solid 125-128 1-25 colorless crystalline solid177-179 1-26 white amorphous solid 465 1-27 white amorphous solid 4391-28 white amorphous solid 477 1-29 light yellow crystalline solid107-110 1-30 colorless crystalline solid 194-197 1-31 colorlesscrystalline solid 154-156 1-31 (hydrochloride) yellow crystalline solid162-165 1-32 colorless crystalline solid 138-140 1-33 colorlesscrystalline solid 191-193 1-34 light yellow crystalline solid 106-1091-35 light yellow crystalline solid 93-96 1-36 light yellow crystallinesolid 110-113 1-37 light yellow amorphous solid 476 1-38 colorlesscrystalline solid 194-196 1-39 colorless crystalline solid 208(dec.)1-40 colorless crystalline solid 74-77 1-41 light yellow amorphous solid70-80 1-42 light yellow amorphous solid 453 1-43 colorless crystallinesolid 143-145 1-44 colorless crystalline solid 135-137 1-45 light yellowamorphous solid 495 1-46 colorless crystalline solid 103-107 1-47colorless crystalline solid 133-134 1-48 white amorphous solid 455 1-49colorless crystalline solid 121-123 1-50 colorless crystalline solid129-130 1-51 light yellow amorphous solid 467 1-52 light yellowamorphous solid 477 1-53 white amorphous solid 495 1-54 colorlesscrystalline solid 166-168 1-55 yellow amorphous solid 66-78 489 1-71colorless crystalline solid 164-166 1-73 light yellow amorphous solid471 1-110 colorless crystalline solid 156-158 1-126 colorlesscrystalline solid 123-125 1-147 white amorphous solid 517 1-164 whiteamorphous solid 530 1-168 colorless crystalline solid 190-192 1-175white amorphous solid 520 1-249 colorless crystalline solid 73-76 1-250colorless crystalline solid 168-170 1-254 colorless crystalline solid169-171 1-257 colorless crystalline solid 195-197 1-259 colorlesscrystalline solid 180-183 1-262 white amorphous solid 465 1-263colorless amorphous solid 475 1-272 colorless crystalline solid 142-1441-273 white amorphous solid 443 1-275 colorless crystalline solid138-140 1-281 colorless crystalline solid 170-172 1-284 colorlesscrystalline solid 59-62 1-290 colorless crystalline solid 144-146 1-293white amorphous solid 476 1-315 white amorphous solid 503 1-319 whiteamorphous solid 513 1-320 colorless crystalline solid 103-105 1-321colorless crystalline solid 138-140 1-322 colorless crystalline solid158-159 1-341 white amorphous solid 501 1-372 white amorphous solid 5291-374 colorless crystalline solid 141-144 1-377 light yellow crystallinesolid 112-114 1-380 colorless crystalline solid 120-122 1-383 whiteamorphous solid 412 1-386 colorless crystalline solid 82-85 1-389 lightyellow crystalline solid  97-100 1-392 colorless crystalline solid141-143 1-395 colorless crystalline solid 205-207 1-398 colorlesscrystalline solid 79-81 1-401 white amorphous solid 425 1-404 whiteamorphous solid 435 1-407 white amorphous solid 451 1-410 light yellowcrystalline solid 81-84 1-413 light yellow crystalline solid 92-95 1-416white amorphous solid 441 1-419 light yellow crystalline solid 75-781-422 white amorphous solid 481 1-425 colorless crystalline solid176-178 1-428 colorless crystalline solid 94-97 1-431 white amorphoussolid 467 1-432 white amorphous solid 465 1-434 colorless crystallinesolid 156-158 1-435 colorless crystalline solid 89-92 1-438 whiteamorphous solid 439 1-441 colorless crystalline solid 90-92 1-444colorless crystalline solid 165-167 1-447 colorless crystalline solid79-81 1-450 colorless crystalline solid 94-96 1-451 white amorphoussolid 465 1-453 colorless crystalline solid 191-193 1-454 colorlesscrystalline solid 178-180 1-457 white amorphous solid 495 1-460 whiteamorphous solid 533 1-463 white amorphous solid 495 1-466 light yellowamorphous solid 481 1-467 white amorphous solid 479 1-468 colorlesscrystalline solid 144-145 1-469 colorless crystalline solid 165-1671-470 colorless crystalline solid 155-156 1-471 colorless crystallinesolid 179-181 1-472 colorless crystalline solid 151-153 1-473 colorlesscrystalline solid 60-62 1-476 colorless crystalline solid 137-139 1-477colorless crystalline solid 70-73 1-480 colorless crystalline solid72-74 1-483 colorless crystalline solid 89-92 1-486 white amorphoussolid 453 1-489 white amorphous solid 467 1-492 white amorphous solid431 1-495 colorless crystalline solid 84-86 1-498 white amorphous solid445 1-501 colorless crystalline solid 86-88 1-504 colorless crystallinesolid 70-73 1-507 colorless crystalline solid 71-74 1-510 whiteamorphous solid 399 1-513 white amorphous solid 461 1-515 whiteamorphous solid 469 1-517 light yellow amorphous solid 529 1-520colorless crystalline solid 193-195 1-523 yellow amorphous solid 5011-526 light yellow amorphous solid 499 1-529 white amorphous solid 5311-532 colorless crystalline solid 87-88 1-535 light yellow crystallinesolid 90-92 1-538 white amorphous solid 532 1-541 colorless crystallinesolid 81-83 1-544 light yellow amorphous solid 549 (ESI⁺) 1-545 whiteamorphous solid 547 1-546 white amorphous solid 575 1-547 light yellowamorphous solid 557 (ESI⁺) 1-550 colorless crystalline solid 65-68 1-553white amorphous solid 547 1-556 colorless crystalline solid 81-83 1-559white amorphous solid 571 1-562 white amorphous solid 563 1-565 whiteamorphous solid 504 1-565 (hydrochloride) colorless crystalline solid96-98 1-568 (hydrochloride) colorless crystalline solid 77-80 1-571light yellow crystalline solid 64-68 1-574 light yellow crystallinesolid 61-65 1-577 light brown amorphous solid 510 1-580 colorlesscrystalline solid 61-64 1-583 light yellow amorphous solid 546 1-586colorless crystalline solid 146-148 1-589 white amorphous solid 4831-592 white amorphous solid 165-167 465 1-593 white amorphous solid 4711-596 white amorphous solid 497 1-599 colorless crystalline solid177-179 1-600 colorless crystalline solid 147 1-603 white amorphoussolid 519 1-606 light yellow amorphous solid 533 1-609 white amorphoussolid 467 1-612 light yellow crystalline solid 107-109 1-618 colorlesscrystalline solid 137-138 1-623 yellow amorphous solid 571 1-624 whiteamorphous solid 531 1-625 white amorphous solid 537 1-626 yellowamorphous solid 559 1-627 white amorphous solid 525 1-629 browncrystalline solid 89-93 1-630 pink amorphous solid 584 1-631 colorlesscrystalline solid 159-160 1-632 white amorphous solid 535 2-1 colorlesscrystalline solid 129-131 2-2 white amorphous solid 483 2-3 colorlesscrystalline solid 89-91 413 2-4 colorless amorphous solid 441 2-5colorless crystalline solid 64-66 2-6 colorless crystalline solid150-152 2-7 light yellow crystalline solid 147-149 2-8 light yellowamorphous solid 467 2-9 colorless crystalline solid 86-89 2-10 colorlesscrystalline solid 68-70 2-11 colorless crystalline solid 113-115 2-12white amorphous solid 64-70 595 2-13 colorless crystalline solid 155-1582-14 light yellow crystalline solid 133-135 2-15 colorless crystallinesolid 107-110 2-16 colorless crystalline solid 184-187 2-17 colorlesscrystalline solid 123-126 2-18 light yellow crystalline solid 82-84 2-19light yellow crystalline solid 74-76 2-20 colorless crystalline solid80-83 2-21 white amorphous solid 51-54 459 3-1 colorless crystallinesolid 156-158 3-1 (R isomer) colorless crystalline solid 75-78 3-1 (Sisomer) colorless crystalline solid 75-77 3-2 colorless crystallinesolid 76-78 3-3 colorless crystalline solid 144-146 3-4 colorlesscrystalline solid 182-184 3-5 colorless crystalline solid 88-90 3-6 (Risomer) colorless crystalline solid 82-85 3-6 (S isomer) colorlesscrystalline solid 82-84 3-7 colorless crystalline solid 85-87 3-8 lightyellow amorphous solid 70-75 455 3-9 colorless crystalline solid 135-1373-10 colorless crystalline solid 156-159 3-11 light yellow crystallinesolid 151-153 3-12 colorless crystalline solid 123-125 3-13 whiteamorphous solid 481 3-14 colorless crystalline solid 156-158 3-15 yellowcrystalline solid 147-149 3-16 colorless crystalline solid 103-105 3-17light yellow crystalline solid 101-103 3-18 colorless crystalline solid112-115 3-19 colorless crystalline solid 186-190 3-20 white amorphoussolid 477 3-21 colorless crystalline solid 488 3-22 brown crystallinesolid 229-232 3-23 colorless crystalline solid 96-99 3-24 colorlesscrystalline solid 74-76 3-25 colorless crystalline solid 60-62 3-26colorless crystalline solid 179-180 3-27 colorless crystalline solid93-95 3-28 light yellow crystalline solid 195-197 3-29 colorlesscrystalline solid 176-177 3-30 colorless crystalline solid 83-85 3-31colorless crystalline solid 240-241 3-32 yellow crystalline solid208-211 3-33 colorless crystalline solid  98-101 3-34 light yellowcrystalline solid 107-109 3-35 white amorphous solid 87-91 540 3-36colorless crystalline solid 134-136 3-37 light yellow crystalline solid153-155 3-38 colorless crystalline solid 101-103 3-39 light yellowamorphous solid  86-101 467 3-40 white amorphous solid 108-110 566 3-41colorless crystalline solid 224-226 3-42 colorless amorphous solid 4263-43 white amorphous solid 442 3-44 white amorphous solid 441 3-45 whiteamorphous solid 457 In Table 4, “dec.” means decomposition temperature.

Test Example 1 Evaluation of Blood Calcium Concentration-decreasingActivity

The blood calcium concentration in a living body is strictly controlledand constantly maintained by intestinal absorption and urinary excretionand release (bone resorption) and adhesion (bone formation) in bonetissues. In an immature rat, which is very active in bone resorption andbone formation, the blood calcium concentration is significantlydecreased by strongly suppressing bone resorption. The boneresorption-suppressing activity of compounds according to the presentinvention was evaluated by administering the compounds to immature ratsand observing decreases in blood calcium concentration as an index ofthe activity.

The test was conducted using 4-week old male Wistar rats fasted for 12to 24 hours. Each compound to be tested was suspended in 0.5% methylcellulose (MC). The suspension was orally administered to the rats at adose of 5 mL/kg. Similarly, rats of a normal control group wereadministered with 0.5% MC alone. Then, blood was drawn from rat jugularvein under ether anesthesia 6 hours after the administration of eachtest compound or 0.5% MC. The blood was immediately centrifuged (10000rpm, 5 minutes) at room temperature to separate serum. The calciumconcentration of each serum was measured by an autoanalyzer (JEOL,JCA-BM2250). Five rats were used for each test group.

The test results are shown in Table 5 below. The evaluation wasconducted by a comparative test with the normal control group and basedon the serum calcium concentration-decreasing rate (%) calculatedaccording to the following formula:

Serum calcium concentration-decreasing rate (%)=(([serum calciumconcentration in normal control group] - [serum calcium concentration intest compound administration group])/[serum calcium concentration innormal control group])×100.

TABLE 5 Administration dose Serum calcium concentration- Test compound(mg/kg) decreasing rate (%) Example 5 10 27.6 Example 9 20 29.3 Example11 20 30.6 Example 14 10 33.2 Example 16 10 27.2

In general, a constant blood calcium concentration should be strictlymaintained, but the blood calcium concentrations were decreased byadministering the compounds according to the present invention. Thisresult suggests that the blood calcium concentration-decreasing activityof the compounds according to the present invention is high.

Test Example 2 Evaluation of Bone Density Decrease-suppressing Activityand Anti-arthritic Activity

In rheumatoid arthritis, not only swelling and pain caused by arthritisbut also systemic bone mass decrease and articular destruction caused bya significant increase in bone resorption are observed. The effects ofthe compounds according to the present invention in suppressing the bonemass decrease and the paw volume increase caused by arthritis wereevaluated using adjuvant arthritis model rats, which exhibit arthritissimilar to human rheumatoid arthritis.

The test was conducted using 8-week old female Lewis rats. Mycobacteriumbutyricum cells which were killed by heat were ground in an agatemortar, suspended in liquid paraffin sterilized by dry heat to aconcentration of 2 mg/mL, and treated with ultrasound to prepare anadjuvant. Under ether anesthesia, rats in a control group other than anormal control group and rats in a test compound administration groupwere intradermally injected with 0.05 mL of this adjuvant each time (0.1mL/rat in total) at two portions of the base of the tail. Starting from14 days after the injection of the adjuvant, each rat was orallyadministered with 5 mL/kg of a test compound suspended in 0.5% MC once aday for 7 days. Similarly, the rats of the control group wereadministered with 0.5% MC alone. On the 21st day after the adjuvantinjection, hind paw volumes were measured by using a paw edema volumedetermining device (MUROMACHI KIKAI, TK-101CMP). Then, the thighbone wasbiopsied. The thighbone was, after removing soft tissues, sufficientlyfixed, dehydrated, and dried using ethanol. The bone density of thethighbone was measured with a bone density analyzer (Aloka, DOS-600EX-IIIR). Five rats were used for each test group.

The test results are shown in Table 6 below.

The evaluation was conducted by comparison tests with the normal controlgroup and the control group and based on the bone densitydecrease-suppressing rate (%) and the paw edema-suppressing rate (%)calculated according to the following formulae:Bone density decrease-suppressing rate (%)=(1−([thighbone bone densityin normal control group]−[thighbone bone density in test compoundadministration group])/([thighbone bone density in normal controlgroup]−[thighbone bone density in control group]))×100Paw edema-suppressing rate (%)=(1−([paw volume of test compoundadministration group]−[paw volume in normal control group])/([paw volumein control group]−[paw volume in normal control group]))×100

TABLE 6 Administration Bone density Paw edema- Test dosedecrease-suppressing suppressing rate compound (mg/kg) rate (%) (%)Example 3 10 57 22 Example 5 10 54 25 Example 9 10 37 11 Example 11 1040 29 Example 14 10 86 12 Example 16 10 70 35

The bone density decrease and the paw volume increase were significantlysuppressed by administering the compounds according to the presentinvention. Thus, advantageous effects of the compounds according to thepresent invention as prophylactic or therapeutic drugs for bonemetabolic diseases and inflammation were confirmed.

Industrial Applicability

The drugs according to the present invention have blood calciumconcentration-decreasing effect and bone mass decrease-suppressingeffect due to their excellent bone resorption-suppressing effects andare low in toxicity. Therefore, the drugs are useful as prophylactic ortherapeutic drugs for bone metabolic diseases, for example,osteoporosis, hypercalcemia, bone metastasis of cancer, periodontaldisease, bone Paget's disease, and osteoarthrosis, in mammals (such ashuman, ape, dog, cat, horse, and hog, in particular, human).

1.4-(cyclopropylmethoxyl)-N-{1-{[(2-hydroxyethel)amino]carbonyl}-2-[4-(trifluoromethoxyl)phenyl]vinyl}benzamide,or a pharmacologically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide,or the pharmacologically acceptable salt thereof according to claim 1,and a pharmacologically acceptable filler or diluent.
 3. A method forthe treatment of a bone metabolic disease, comprising administering aneffective amount of the4-(cyclopropylmethoxy)-N-{1-}[(2-hydroxyethy)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamideor pharmacologically acceptable salt according to claim 1 to a mammal.4. A method for the treatment of osteoporosis, comprising administeringan effective amount of the4-(cyclopropylmethoxy)-N-{1-{[(2-hydroxyethy)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamideor pharmacologically acceptable salt according to claim 1 to a mammal.5. The method according to claim 3, wherein the bone metabolic diseaseis osteoporosis.
 6. The method according to claim 3, wherein the bonemetabolic disease is hypercalcemia.
 7. The method according to claim 3,wherein the effective amount of the composition is a dose from 0.001mg/kg to 100 mg/kg.